JP6168773B2 - Substituted imidazoquinoxaline - Google Patents

Description

  The present invention relates to a substituted imidazoquinoxaline compound of general formula (I) as described and defined herein, a process for the preparation thereof, a pharmaceutical composition containing the compound and a combined medicament, for the treatment or prevention of disease. It relates to the use of the compounds for the manufacture of a pharmaceutical composition for the preparation, and to intermediate compounds useful for the preparation of the compounds.

The present invention relates to compounds that inhibit Mps-1 (monopolar spindle 1) kinase (also known as tyrosine threonine kinase, TTK). Mps-1 is a bispecific serine / threonine kinase that plays an important role in the activation of mitotic checkpoints (also known as spindle checkpoints, spindle assembly checkpoints) It ensures proper chromosome distribution during mitosis [Abrieu A et al., Cell, 2001, 106, 83-93]. All dividing cells must ensure equal separation of replicating chromosomes into two daughter cells. Upon entering mitosis, the chromosome is bound to the spindle microtubules in its centromere. The mitotic checkpoint is a surveillance mechanism that is active as long as unbound centromeres are present, preventing mitotic cells from entering late stages, and cell division with unlinked chromosomes. [Suijkerbuijk SJ and Kops GJ, Biochemica et Biophysica Acta, 2008, 1786, 24-31; Musacchio A and Salmon ED, Nat Rev Mol Cell Biol., 2007, 8, 379-93]. Once all centromeres have joined the mitotic spindle in the correct amphitelic, i.e. bipolar manner, the checkpoint is satisfied and the cell enters anaphase and progresses through mitosis . Mitotic checkpoints include members of the MAD (mitotic arrest deficient, MAD 1-3) and Bub (Budding uninhibited by benzimidazole, Bub 1-3) families, motor proteins CENP-E, Mps-1 kinase and other components It consists of a complex network of many essential proteins. Many of these are overexpressed in proliferating cells (eg, cancer cells) and tissues [Yuan B et al., Clinical Cancer Research, 2006, 12, 405-10]. The essential role of Mps-1 kinase activity in mitotic checkpoint signaling has been demonstrated by shRNA silencing, chemical genetics and chemical inhibitors of Mps-1 kinase [Jelluma N et al., PLos ONE , 2008, 3, e2415; Jones MH et al., Current Biology, 2005, 15, 160-65; Dorer RK et al., Current Biology, 2005, 15, 1070-76; Schmidt M et al., EMBO Reports, 2005, 6, 866- 72].

  There is ample evidence to link a reduced, incomplete mitotic checkpoint mechanism with aneuploidy and tumorigenesis [Weaver BA and Cleveland DW, Cancer Research, 2007, 67, 10103-5; King RW, Biochimica et al. Biophysica Acta, 2008, 1786, 4-14]. In contrast, complete inhibition of the mitotic checkpoint has been recognized to result in severe chromosome segregation and induction of apoptosis in tumor cells [Kops GJ et al., Nature Reviews Cancer, 2005, 5, 773. -85; Schmidt M and Medema RH, Cell Cycle, 2006, 5, 159-63; Schmidt M and Bastians H, Drug Resistance Updates, 2007, 10, 162-81]. Thus, the suppression of mitotic checkpoints through pharmacological inhibition of Mps-1 kinase or other components of mitotic checkpoints can result in solid tumors such as carcinomas and sarcomas and leukemia and lymphoid tumors or uncontrolled cell growth A new approach to the treatment of other diseases related to

  WO97 / 019079 (Biomedica Foscama Industria Chimico-Farmaceutica S.P.A.) relates to imidazo [1,2-a] quinoxalin-4-amine which is active as an adenosine antagonist as a therapeutically active compound for mental disorders and neurological disorders of the central nervous system. The imidazo [1,2-a] quinoxalin-4-amine is substituted at the 1-position by a hydrogen atom or a methyl group.

  WO02 / 060386 (Bristol-Myers Squibb Company) relates to methods for the prevention and treatment of inflammatory and immune related diseases or disorders using inhibitors of IκB kinase (IKK), which include, inter alia, certain IKK inhibitors, 4- ( It relates to 2'-aminoethyl) amino-1,8-dimethylimidazo (1,2-a) quinoxaline and benzimidazoquinoxaline.

WO2007 / 109813 (Novartis AG) relates to a composition comprising an imidazoquinoxaline compound as an immunomodulator and also relates to a method of administering the composition for improving the immune response of a subject. The imidazoquinoxaline is substituted at the 4-position by an —NH ₂ group or a bis (4-methoxybenzyl) amino group.

WO2008 / 117225 (Mutabilis SA) relates to imidazolo-heteroaryl derivatives that inhibit the activity of Dlta enzyme in Gram positive bacteria and are useful for treating Gram positive bacterial infections. The imidazolo-heteroaryl derivative includes imidazoquinoxaline having a —NHCH ₂ CH ₂ CH ₂ OR 5 substituent (R 5 is H or a substituent as defined in the specification) in the 4-position.

  WO2009 / 024824 A1 (AstraZeneca UK Limited) is a 2-anilinopurine-8- having inhibitory activity against spindle checkpoint kinase tyrosine threonine kinase (TTK) / monopolar spindle 1 (Mps-1) for the treatment of proliferative diseases On on.

  However, any of the state of the art is a substituted imidazoquinoxaline compound of the general formula (I) of the present invention, or a stereoisomer thereof, as described and defined herein and also referred to below as “compound of the present invention” It does not describe tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, or their pharmacological activity. It has now been discovered that the compounds of the present invention have surprising and advantageous properties, which constitute the basis of the present invention.

  In particular, the above compounds of the present invention have been surprisingly found to effectively inhibit Mps-1 kinase, and thus uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune responses or inappropriate A disease of a cellular inflammatory response, or a disease associated with uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response, in particular uncontrolled cell growth, proliferation and Diseases in which survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is mediated by Mps-1 kinase, eg hematological tumors, solid tumors and / or metastases thereof, eg leukemia and myelodysplastic syndrome , Malignant lymphoma, head and neck tumors including brain tumors and brain metastases, non-small and small cell lung tumors, gastrointestinal tumors, endocrine tumors, breast tumors including mammary gland and other gynecological tumors, nephroma , Urinary system tumors including bladder and prostate tumors, may be used in the treatment or prevention of skin tumors and sarcomas and / or metastases thereof.

DESCRIPTION OF THE INVENTION According to a first aspect, the present invention provides a compound of general formula (I)

[Where:
R ¹ is C ₁ -C ₁₀ - alkyl -, halo -C ₁ -C ₁₀ - alkyl _{-, HO-C 1 -C 10} - alkyl -, C ₁ -C ₁₀ - alkoxy -C ₁ -C ₁₀ - alkyl - Aryloxy-C ₁ -C ₁₀ -alkyl-, halo-C ₁ -C ₁₀ -alkoxy-C ₁ -C ₁₀ -alkyl-, C ₂ -C ₁₀ -alkenyl-, C ₂ -C ₁₀ -alkynyl-, C ₃ -C ₁₀ - cycloalkyl -, 3-to 10-membered heterocycloalkyl -, aryl -, heteroaryl -, C ₁ -C ₆ - alkylene - aryl -, C ₁ -C ₆ - alkylene - heteroaryl - , -C ₁ -C ₆ -alkylene-C ₃ -C ₁₀ -cycloalkyl, -C ₁ -C ₆ -alkylene- (3- to 10-membered heterocycloalkyl), -C ₁ -C ₆ -alkylene-aryl A -C ₁ -C ₆ -alkylene-heteroaryl group,
Here, the following substituents optionally above groups: halo -, hydroxy -, cyano -, nitro -, C ₁ -C ₆ - alkyl -, halo -C ₁ -C ₆ - alkyl -, C ₁ -C ₆ -alkoxy-, halo-C ₁ -C ₆ -alkoxy-, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl -, C ₃ -C ₁₀ - cycloalkyl -, 3-to 10-membered heterocycloalkyl -, - C (= O) OH, -C (= O) OC 1 -C 6 - alkyl, -C (= O ) OC ₃ -C ₁₀ -cycloalkyl, -OC (= O) -C ₁ -C ₆ -alkyl, -OC (= O) -C ₃ -C ₁₀ -cycloalkyl, -N (H) C (= O ) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -N (H) S (= O) ₂ R ⁸ , -N (C ₁ -C ₆ -alkyl) S ( = O) ₂ R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -OC (= O) NR ⁹ R ¹⁰ , -N (H) C (= O) OR ⁸ , -N (C ₁ -C ₆ -Alkyl) C (= O) OR ⁸ , -N (H) C (= O) NR ⁹ R ¹⁰ , -N (C ₁ -C ₆ -alkyl) C (= O) NR ⁹ R ¹⁰ , -SR ⁸ , -S (= O) R ⁸ , -S (= O) ₂ R ⁸ , -S (= O) ₂ NR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ May be replaced with
R ² is -CN, -NR ⁹ R ¹⁰ , -OR ⁹ , C ₂ -C ₁₀ -alkenyl-, C ₂ -C ₁₀ -alkynyl-, aryl-, heteroaryl-, C ₁ -C ₆ -alkylene-aryl -, A C ₁ -C ₆ -alkylene-heteroaryl-group,
Wherein the above groups optionally have the following substituents: halo-, hydroxy-, cyano-, nitro-, C ₁ -C ₆ -alkyl-, halo-C ₁ -C ₆ -alkyl-, HO-C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkoxy-, halo-C ₁ -C ₆ -alkoxy-, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkyl-C (= O) N (H) -C ₁ -C ₆ -alkyl-, C ₃ -C ₁₀ -cycloalkyl-, 3-to 10-membered heterocycloalkyl -, - C (= O) -C 1 -C 6 - alkyl, -C (= O) OH, -C (= O) OC 1 -C 6 - alkyl, -C (= O) OC ₃ -C ₁₀ -cycloalkyl, -OC (= O) -C ₁ -C ₆ -alkyl, -OC (= O) -C ₃ -C ₁₀ -cycloalkyl, -N (H) C (= O) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -N (H) S (= O) ₂ R ⁸ , -N (C ₁ -C ₆ -alkyl ) S (= O) ₂ R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -OC (= O) NR ⁹ R ¹⁰ , -N (H) C (= O) OR ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) OR ⁸ , -N (H) C (= O) NR ⁹ R ¹⁰ , -N (C ₁ -C ₆ -alkyl) C (= O) NR ⁹ R ¹⁰ , -SR ⁸ , -S (= O) R ⁸ , -S (= O) ₂ R ⁸ , -S (= O) ₂ NR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ may be substituted one or more times with the same or different substituents,
R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ are each independently a hydrogen atom, a halogen atom, hydroxy, cyano, nitro or a group selected from: C ₁ -C ₆ -alkyl, halo-C _1- C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halo-C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl, 3- to ₁₀ -membered heterocycloalkyl, -C (= O) OH, -C (= O) OC ₁ -C ₆ -alkyl, -C (= O) OC ₃ -C ₁₀ -cycloalkyl, -N (H) C (= O) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -N (H) S (= O) ₂ R ⁸ , -N (C ₁ -C ₆ -alkyl) S (= O) ₂ R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -OC (= O) NR ⁹ R ¹⁰ , -N (H) C (= O) OR ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) OR ⁸ , -N (H) C (= O) NR ⁹ R ¹⁰ , -N (C ₁ -C ₆ -alkyl) C (= O) NR ⁹ R ¹⁰ , -SR ⁸ , -S (= O) R ⁸ , -S (= O) ₂ R ⁸ , -S (= O) ₂ NR ^{9 R 10, -NR 9 R 10} , C 2 -C 6 - alkenyl, C ₂ -C ₆ - alkynyl, aryl, heteroaryl, C ₁ -C ₆ - A Killen - aryl, C ₁ -C ₆ - alkylene - heteroaryl, -C ₁ -C ₆ - alkylene -C ₃ -C ₁₀ - cycloalkyl or C ₁ -C ₆ - alkylene -3-to 10-membered heterocycloalkyl Group,
Wherein the above group optionally has the following substituents: halogen, hydroxy, cyano, nitro, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halo- C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl , 3-to 10-membered heterocycloalkyl, -C (= O) OH, -C (= O) OC 1 -C 6 - _{alkyl, -C (= O) OC 3} -C 10 - cycloalkyl, -N (H) C (= O) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -N (H) S (= O) ₂ R ⁸ , -N (C _1- C ₆ -alkyl) S (= O) ₂ R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -OC (= O) NR ⁹ R ¹⁰ , -N (H) C (= O) OR ⁸ ,- N (C ₁ -C ₆ -alkyl) C (= O) OR ⁸ , -N (H) C (= O) NR ⁹ R ¹⁰ , -N (C ₁ -C ₆ -alkyl) C (= O) NR ⁹ R ¹⁰ , -SR ⁸ , -S (= O) R ⁸ , -S (= O) ₂ R ⁸ , -S (= O) ₂ NR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ May be substituted one or more times by different substituents,
R ⁸ , R ⁹ and R ¹⁰ are each independently a hydrogen atom, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, HO-C ₁ -C ₆ -alkyl-, cyano-C _1- C ₆ -alkyl-, C ₂ -C ₁₀ -alkynyl-C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, H ₂ NC (= O) -C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkyl-N (H) C (= O) -C ₁ -C ₆ -alkyl- _{, H 2 NS (= O)} 2 -C 1 -C 6 - alkyl -, C ₂ -C ₆ - alkenyl, C ₂ -C ₆ - alkynyl, C ₃ -C ₁₀ - cycloalkyl, 3-to 10-membered Heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ -alkylene-aryl, -C ₁ -C ₆ -alkylene-heteroaryl, -C ₁ -C ₆ -alkylene-C ₃ -C ₁₀ -cycloalkyl,- A C ₁ -C ₆ -alkylene-3- to 10-membered heterocycloalkyl group,
Where the above C ₃ -C ₁₀ -cycloalkyl group is optionally halogen atom, cyano, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, HO-C ₁ -C ₆ -alkyl May be substituted one or more times by a C ₁ -C ₆ -alkoxy, C ₃ -C ₁₀ -cycloalkyl, aryl or heteroaryl group,
Wherein the above aryl group optionally has the following substituents: halogen, hydroxy, cyano, nitro, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halo -C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cyclo alkyl, 3-to 10-membered heterocycloalkyl, -C ₁ -C ₆ - alkylene -3-to 10-membered heterocycloalkyl, -C (= O) OH, -C (= O) OC 1 -C 6 -Alkyl, -C (= O) OC ₃ -C ₁₀ -cycloalkyl, -N (H) C (= O) -C ₁ -C ₆ -alkyl, -N (H) C (= O) -heteroaryl , -N (C ₁ -C ₆ -alkyl) C (= O) -C ₁ -C ₆ -alkyl, -N (H) S (= O) ₂ -C ₁ -C ₆ -alkyl, -N (C ₁ -C ₆ - _{alkyl) S (= O) 2 -C} 1 -C 6 - _{alkyl, -C (= O) NH 2} , -C (= O) N (H) -C 1 -C 6 - alkyl, -C (= O) N (C ₁ -C ₆ -alkyl) ₂ , -OC (= O) NH ₂ , -OC (= O) N (H) -C ₁ -C ₆ -alkyl, -OC (= O) N (C ₁ -C ₆ -alkyl) ₂ , -N (H) C (= O) OC ₁ -C ₆ -alkyl, -N (C ₁ -C ₆ -alkyl) C (= O) OC ₁ -C ₆ -alkyl, -N (H) C (= O) NH ₂ , -N (H) C (= O) N (H) -C ₁ -C ₆ -alkyl, -N (H) C (= O) N (C ₁ -C ₆ -alkyl) ₂ , -N (C ₁ -C ₆ -alkyl) C (= O) NH ₂ , -N (C ₁ -C ₆ -alkyl) C (= O) N (H) -C ₁ -C ₆ -alkyl, -N (C ₁ -C ₆ -alkyl) C (= O) N (C ₁ -C ₆ -alkyl) ₂ , -SC ₁ -C ₆ -alkyl, -S (= O) -C ₁ -C ₆ -alkyl, -S (= O ) ₂ -C ₁ -C ₆ -alkyl, -S (= O) ₂ NH ₂ , -S (= O) ₂ N (H) -C ₁ -C ₆ -alkyl, -S (= O) ₂ N ( C ₁ -C ₆ -alkyl) ₂ , -NH ₂ , -N (H) -C ₁ -C ₆ -alkyl, -N (C ₁ -C ₆ -alkyl) ₂ May be substituted one or more times, or
R ⁹ and R ¹⁰ together with the nitrogen to which they are attached are 3- to 10-membered heterocycloalkyl groups;
However,
R ¹ is -CH ₂ CH ₂ CH ₂ OH,
-CH ₂ CH ₂ CH ₂ O (C = O) -R _a ,
-CH ₂ CH ₂ CH ₂ O (C = O) -OR _a ,
-CH ₂ CH ₂ CH ₂ O (C = O) -CHR _a NR _b R _c
Where R _a , R _b , R _c are the same or different and are H, C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl, C ₂ -C ₁₀ -alkynyl, phenyl and Selected from the group consisting of heteroaryl]
Or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

The terms described herein preferably have the following meanings:
The term “halogen atom” or “halo” should be understood to mean a fluorine, chlorine, bromine or iodine atom.

The term “C ₁ -C ₁₀ -alkyl” is preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, in particular 1, 2, 3, 4, 5 or 6 Straight chain or branched saturated monovalent hydrocarbon group having a carbon atom of, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1 -Methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1- Ethyl butyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, 1,2-dimethylbutyl group or isomers thereof. It should be understood as meaning. In particular, the above groups have 1, 2 or 3 carbon atoms (“C ₁ -C ₃ -alkyl”) and are methyl, ethyl, n-propyl or isopropyl.

The term “halo-C ₁ -C ₁₀ -alkyl” is preferably a straight-chain or branched saturated monovalent hydrocarbon group, the term “C ₁ -C ₁₀ -alkyl” is defined above, and 1 It should be understood to mean a group in which more than one hydrogen atom is replaced by the same or different halogen atoms, ie one halogen atom is independent of another halogen atom. In particular, the halogen atom is F. A halo-C ₁ -C ₁₀ -alkyl group is, for example, —CF ₃ , —CHF ₂ , —CH ₂ F, —CF ₂ CF ₃ or —CH ₂ CF ₃ .

The term “C ₁ -C ₁₀ -alkoxy” is preferably a straight-chain or branched saturated monovalent hydrocarbon radical of the formula —O-alkyl, the term “alkyl” as defined above, eg methoxy , Ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentoxy, isopentoxy or n-hexoxy groups, or isomers thereof.

The term “halo-C ₁ -C ₁₀ -alkoxy” is preferably a linear or branched saturated monovalent C ₁ -C ₁₀ -alkoxy group as defined above, wherein one or more hydrogen atoms are identical. Or it should be understood to mean a group substituted with a different rogen atom. In particular, the halogen atom is F. The halo-C ₁ -C ₁₀ -alkoxy group is, for example, —OCF ₃ , —OCHF ₂ , —OCH ₂ F, —OCF ₂ CF ₃ or —OCH ₂ CF ₃ .

The term “C ₁ -C ₁₀ -alkoxy-C ₁ -C ₁₀ -alkyl” is preferably a linear or branched saturated monovalent alkyl group as defined above, wherein one or more hydrogen atoms are as defined above. Should be understood as meaning groups substituted by the same or different C ₁ -C ₁₀ -alkoxy groups, as defined for example for example methoxyalkyl, ethoxyalkyl, propyloxyalkyl, isopropoxyalkyl, butoxy Alkyl, isobutoxyalkyl, tert-butoxyalkyl, sec-butoxyalkyl, pentyloxyalkyl, isopentyloxyalkyl, hexyloxyalkyl groups (where the term “C ₁ -C ₁₀ -alkyl” is defined above) ), Or isomers thereof.

The term “halo-C ₁ -C ₁₀ -alkoxy-C ₁ -C ₁₀ -alkyl” is preferably a straight-chain or branched saturated monovalent C ₁ -C ₁₀ -alkoxy-C ₁ -C ₁₀ as defined above. -Alkyl groups, which are to be understood as meaning groups in which one or more hydrogen atoms are replaced by the same or different halogen atoms. In particular, the halogen atom is F. The above halo-C ₁ -C ₁₀ -alkoxy-C ₁ -C ₁₀ -alkyl groups are, for example, —CH ₂ CH ₂ OCF ₃ , —CH ₂ CH ₂ OCHF ₂ , —CH ₂ CH ₂ OCH ₂ F, — CH ₂ CH ₂ OCF ₂ CF ₃ or —CH ₂ CH ₂ OCH ₂ CF ₃ .

The term “C ₂ -C ₁₀ -alkenyl” is preferably a straight chain containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms or It should be understood to mean a branched monovalent hydrocarbon radical, in particular having 2 or 3 carbon atoms (“C ₂ -C ₃ -alkenyl”). It is understood that if the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated. Examples of the alkenyl group include vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl, homoallyl, (E) -but-2-enyl, (Z) -but-2- Enyl, (E) -but-1-enyl, (Z) -but-1-enyl, pent-4-enyl, (E) -pent-3-enyl, (Z) -pent-3-enyl, (E ) -Pent-2-enyl, (Z) -pent-2-enyl, (E) -pent-1-enyl, (Z) -pent-1-enyl, hex-5-enyl, (E) -hex- 4-enyl, (Z) -hex-4-enyl, (E) -hex-3-enyl, (Z) -hex-3-enyl, (E) -hex-2-enyl, (Z) -hex- 2-enyl, (E) -hex-1-enyl, (Z) -hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl (E) -1-methylprop-1-enyl, (Z) -1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3 -Methyl To-2-enyl, (E) -2-methylbut-2-enyl, (Z) -2-methylbut-2-enyl, (E) -1-methylbut-2-enyl, (Z) -1-methylbut- 2-enyl, (E) -3-methylbut-1-enyl, (Z) -3-methylbut-1-enyl, (E) -2-methylbut-1-enyl, (Z) -2-methylbut-1- Enyl, (E) -1-methylbut-1-enyl, (Z) -1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl, 1-methylpent-4-enyl, 4-methylpent-3-enyl, (E) -3 -Methylpent-3-enyl, (Z) -3-methylpent-3-enyl, (E) -2-methylpent-3-enyl, (Z) -2-methylpent-3-enyl, (E) -1-methylpent -3-enyl, (Z) -1-methylpent-3-enyl, (E) -4-methylpent-2-enyl, (Z) -4-methylpent-2-enyl, ( E) -3-methylpent-2-enyl, (Z) -3-methylpent-2-enyl, (E) -2-methylpent-2-enyl, (Z) -2-methylpent-2-enyl, (E) -1-methylpent-2-enyl, (Z) -1-methylpent-2-enyl, (E) -4-methylpent-1-enyl, (Z) -4-methylpent-1-enyl, (E) -3 -Methylpent-1-enyl, (Z) -3-methylpent-1-enyl, (E) -2-methylpent-1-enyl, (Z) -2-methylpent-1-enyl, (E) -1-methylpent -1-enyl, (Z) -1-methylpent-1-enyl, 3-ethylbut-3-enyl, 2-ethylbut-3-enyl, 1-ethylbut-3-enyl, (E) -3-ethylbut-2 -Enyl, (Z) -3-ethylbut-2-enyl, (E) -2-ethylbut-2-enyl, (Z) -2-ethylbut-2-enyl, (E) -1-ethylbut-2-enyl (Z) -1-ethylbut-2-enyl, (E) -3-ethylbut-1-enyl, (Z) -3-ethylbut-1-enyl, 2-ethylbut-1-enyl, (E) -1 -Ethylbut-1-enyl, (Z) 1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl, 2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl, (E) -2 -Propylprop-1-enyl, (Z) -2-propylprop-1-enyl, (E) -1-propylprop-1-enyl, (Z) -1-propylprop-1-enyl, (E) -2-isopropylprop-1-enyl, (Z) -2-isopropylprop-1-enyl, (E) -1-isopropylprop-1-enyl, (Z) -1-isopropylprop-1-enyl, ( E) -3,3-dimethylprop-1-enyl, (Z) -3,3-dimethylprop-1-enyl, 1- (1,1-dimethylethyl) ethenyl, buta-1,3-dienyl, penta 1,4-dienyl, hexa-1,5-dienyl or methylhexadienyl group. In particular, the above group is vinyl or allyl.

The term “C ₂ -C ₁₀ -alkynyl” is preferably a straight chain containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms or It should be understood to mean a branched monovalent hydrocarbon radical, in particular having 2 or 3 carbon atoms (“C ₂ -C ₃ -alkynyl”). The above C ₂ -C ₁₀ -alkynyl groups include, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1- Inyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3- Methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methyl-pent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1- Methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2- Nyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl group. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

The term “C ₃ -C ₁₀ -cycloalkyl” preferably represents a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. In particular, having 3, 4, 5 or 6 carbon atoms (“C ₃ -C ₆ -cycloalkyl”). The above C ₃ -C ₁₀ -cycloalkyl group is, for example, a monocyclic hydrocarbon ring, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl group, or a bicyclic ring Formula hydrocarbon rings, for example perhydropentalenylene or decalin rings. Said cycloalkyl ring can optionally contain one or more double bonds, for example cycloalkenyl, for example cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl. A group, wherein the bond between the ring and the rest of the molecule may be any carbon atom of the ring, which may be saturated or unsaturated.

The term “3- to 10-membered heterocycloalkyl” is preferably 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms and C (═O), O, S, S (= O), S (= O) ₂ , NH, NR ′ where R ′ is C ₁ -C ₆ -alkyl, —C ₁ -C ₆ -alkyl-aryl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ heterocycloalkyl), C (= O) R ⁹ , C (= O) NR ¹⁰ R ¹¹ , -S (= O) ₂ R ⁹ , -S (= O) understood to mean a saturated or partially unsaturated monovalent monocyclic or bicyclic hydrocarbon ring containing one or more heteroatom-containing groups selected from the group ₂ NR ¹⁰ R ¹¹ It should be understood that when R ′ is a C ₃ -C ₆ heterocycloalkyl group, the C ₃ -C ₆ heterocycloalkyl group is present only once. In particular, the above rings can contain 2, 3, 4 or 5 carbon atoms and can contain the above heteroatom-containing groups (“3- to 6-membered heterocycloalkyl”), and more Specifically, the ring may contain 4 or 5 carbon atoms and one or more of the above heteroatom-containing groups (“5- to 6-membered heterocycloalkyl”). The above heterocycloalkyl rings are, for example, monocyclic heterocycloalkyl rings such as oxiranyl, oxetanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, oxopyrrolidinyl, imidazolidinyl, oxoimidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydro Pyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 4-methylpiperazinyl, trithianyl or quinuclidinyl group. In some cases, the heterocycloalkyl ring may contain one or more double bonds, such as 4H-pyranyl, 2H-pyranyl, 3H-diazilinyl, 2,5-dihydro-1H-pyrrole, [1,3] dioxolyl. 4H- [1,3,4] thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothiophenyl, 2,3-dihydrothiophenyl, 4,5-dihydrooxa It may be a zolyl or 4H- [1,4] thiazinyl group, or it may be benzofused.

The term “aryl” is preferably a monovalent aromatic or partially aromatic monocyclic or bicyclic containing 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms. Alternatively, it should be understood as meaning a tricyclic hydrocarbon ring (“C ₆ -C ₁₄ -aryl” group), in particular a ring with 6 carbon atoms (“C ₆ -aryl” group) ), For example, a phenyl or biphenyl group, or a ring having 9 carbon atoms (“C ₉ -aryl” group), for example, an indanyl or indenyl group, or a ring having 10 carbon atoms (“C ₁₀ - aryl "group), for example, tetralinyl, dihydronaphthyl or naphthyl group, or a ring having 13 carbon atoms (" C ₁₃ - aryl "group), for example, a fluorenyl group, or 14 carbon atoms A ring having a “C ₁₄ -aryl” group, for example, an anthranyl group.

  The term “heteroaryl” is preferably a monovalent aromatic monocyclic or bicyclic aromatic ring having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms. Is understood to mean a system (a “5- to 14-membered heteroaryl” group), in particular having at least 5 or 6 or 9 or 10 atoms and can be identical or different. Containing, for example, oxygen, nitrogen or sulfur, which can be monocyclic, bicyclic or tricyclic, and in each case benzo-fused Good. In particular, heteroaryl includes thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and benzo derivatives thereof such as benzofuranyl, benzothienyl, benzoxazolyl , Benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc .; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. and benzo derivatives thereof such as quinolinyl, quinazolinyl, isoquinolinyl, etc .; or azosinyl , Indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoki It is selected from salinyl, naphthopyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl or oxepinyl. More specifically, heteroaryl is selected from pyridyl, benzofuranyl, benzisoxazolyl, indazolyl, quinazolinyl, thienyl, quinolinyl, benzothienyl, pyrazolyl or furanyl. Alternatively, the heteroaryl can be a 1,3-benzodioxolyl or 1,4-benzodioxinyl group.

The term “alkylene” is understood to mean an optionally substituted hydrocarbon chain (or tether), preferably having 1, 2, 3, 4, 5 or 6 carbon atoms, ie -CH optionally substituted ₂ by - ( "methylene" or "a member tether", or, for example, -C (Me) ₂ -), - CH ₂ -CH ₂ - ( "ethylene", "dimethylene", or " `` Two-membered tether ''), --CH <sub>2</sub> --CH <sub>2</sub> --CH <sub>2-</sub> (`` propylene '', `` trimethylene '' or `` three-membered tether '')), --CH ₂ --CH ₂ --CH ₂ --CH _2- (`` butylene '', "tetramethylene", or "four-membered _{tether"), - CH 2 -CH 2 -CH} 2 -CH 2 -CH 2 - ( "pentylene", "pentamethylene" or "five-membered tether"), or, -CH ₂ —CH ₂ —CH ₂ —CH ₂ —CH ₂ —CH ₂ — (“hexylene”, “hexamethylene” or “six-membered tether”) group. In particular, alkylene tethers have 1, 2, 3, 4 or 5 carbon atoms, more specifically 1 or 2 carbon atoms.

The term “C ₁ -C ₆ ” as used throughout this specification is, for example, “C ₁ -C ₆ -alkyl”, “C ₁ -C ₆ -haloalkyl”, “C ₁ -C”. _In the context of the definition of “ ₆ -alkoxy” or “C ₁ -C ₆ -haloalkoxy”, 1 to 6 qualifying carbon atoms, ie 1, 2, 3, 4, 5 or 6 carbon atoms It should be understood to mean an alkyl group having. Furthermore, the above term “C ₁ -C ₆ ” should be construed as any subrange including it, eg, C ₁ -C _{6 ,} C ₂ -C _{5 ,} C ₃ -C _{4 ,} C ₁ -C _{2 ,} C ₁ -C _{3 ,} C ₁ -C _{4 ,} C ₁ -C ₅ C ₁ -C ₆ , especially C ₁ -C _{2 ,} C ₁ -C _{3 ,} C ₁ -C _{4 ,} C _1- C _{5 ,} C ₁ -C ₆ , more specifically C ₁ -C ₄ , even more specifically in the case of “C ₁ -C ₆ -haloalkyl” or “C ₁ -C ₆ -haloalkoxy” Is C ₁ -C ₂ .

Similarly, as used herein, the term “C ₂ -C ₆ ” as used throughout this specification includes, for example, “C ₂ -C ₆ -alkenyl” and “C ₂ In the context of the definition "-C ₆ -alkynyl", meaning an alkenyl or alkynyl group having 2 to 6 limiting values of carbon atoms, ie 2, 3, 4, 5 or 6 carbon atoms; Should be understood. Furthermore, the above term “C ₂ -C ₆ ” should be construed as any subrange contained therein, for example, C ₂ -C _{6 ,} C ₃ -C _{5 ,} C ₃ -C _{4 ,} C ₂ -C _{3 ,} C ₂ -C _{4 and} C ₂ -C _{5 ,} more specifically C ₂ -C ₃ .

Furthermore, as used herein, the term “C ₃ -C ₁₀ ” as used throughout this specification is related to, for example, the definition of “C ₃ -C ₁₀ -cycloalkyl”. In the context of a cycloalkyl group having a limit of 3 to 10 carbon atoms, i.e. 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. In particular, it has 3, 4, 5 or 6 carbon atoms. Furthermore, the above term “C ₃ -C ₁₀ ” should be understood as any sub-range included therein, for example, C ₃ -C _{10 ,} C ₄ -C _{9 ,} C ₅ -C _{8 ,} C ₆ -C ₇ , in particular C ₃ -C ₆ .

  As used herein, the term “one or more times” means, for example, “one time, two times, three times, four times or five times” in the definition of a substituent of a compound of the general formula of the invention. In particular, it is understood to mean once, twice, three times or four times, more specifically once, twice or three times, even more specifically once or twice.

  Where a compound, salt, polymorph, hydrate, solvate, etc. is used in the plural form herein, this is a single compound, salt, polymorph, hydrate, solvate Is understood to mean.

  The compounds of the present invention can contain one or more asymmetric centers depending on the position and nature of the various substituents desired. Asymmetric carbon atoms can exist in the (R) or (S) configuration, resulting in a racemic mixture in the case of a single asymmetric center and a diastereomeric mixture in the case of multiple asymmetric centers. be able to. In certain cases, asymmetry can also be caused by limited rotation around a given bond, eg, a central bond adjacent to two substituted aromatic rings of a particular compound. .

  Substituents on the ring can also exist in either cis or trans form. All such configurations (including enantiomers and diastereomers) are intended to be included within the scope of the present invention.

  Preferred compounds are those that produce a more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic mixtures or diastereomeric mixtures of the compounds of the invention are also included within the scope of the invention. Purification and separation of such materials can be accomplished by standard techniques known in the art.

  Optical isomers can be obtained, for example, by resolution of racemic mixtures by conventional methods by formation of diastereoisomeric salts or formation of covalent diastereomers using optically active acids or bases. Examples of suitable acids are tartaric acid, diacetyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. A mixture of diastereoisomers can be separated into individual diastereomers based on their physical and / or chemical differences, for example, by chromatography or fractional crystallization, by methods known in the art. it can. The optically active base or acid is then released from the separated diastereomeric salt. Different methods for the separation of enantiomers involve the use of chiral chromatography (eg, chiral HPLC columns) with or without conventional derivatization optimally chosen to maximize the separation of enantiomers. Suitable chiral HPLC columns are manufactured by Daicel, for example, Chiralcel OD and Chiralcel OJ, among many others, all conventionally selectable. Enzymatic separation with or without derivatization is also useful. The optically active compounds of the present invention can also be obtained by chiral synthesis using optically active starting materials.

  Reference is made to IUPAC rule section E (Pure Appl Chem 45, 11-30, 1976) to limit the different types of isomers.

  The present invention includes all possible stereoisomers of the compounds of the present invention as a single stereoisomer or as any mixture in any ratio of the stereoisomers. The separation of a single stereoisomer of a compound of the invention, for example a single enantiomer or a single diastereomer, is carried out by any suitable state-of-the-art method such as chromatography, in particular, for example, chiral chromatography. be able to.

  Furthermore, the compounds of the present invention may exist as tautomers. For example, any compound of the invention containing a pyrazole group as a heteroaryl group can exist as a 1H tautomer or 2H tautomer, or even as a mixture of any amount of two tautomers. Or any compound of the invention containing a triazole group may be a 1H tautomer, a 2H tautomer or a 4H tautomer, or even a 1H, 2H and 4H tautomer as described below. It can be present as any amount of mixture.

  The present invention includes all possible tautomers of the compounds of the present invention as a single tautomer or as any mixture in any ratio of the above tautomers.

  Furthermore, the compounds of the invention can exist as N-oxides, which are defined as those in which at least one nitrogen atom of the compounds of the invention is oxidized. The present invention includes all such possible N-oxides.

  The invention also relates to useful forms of the compounds as disclosed herein, eg, useful forms are metabolites, hydrates, solvates, prodrugs, salts, especially pharmaceuticals. Above acceptable salts and coprecipitates.

  The compounds of the present invention can exist as hydrates or solvates, where the compounds of the present invention comprise a polar solvent, in particular, for example, water, methanol or ethanol, as a structural element of the compound's crystal lattice. The amount of polar solvent, especially water, can be present in a stoichiometric or non-stoichiometric ratio. Stoichiometric solvates, such as hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. Each thing is possible. The invention includes all such hydrates or solvates.

  Furthermore, the compounds of the invention can exist in free form, eg free base or free acid, or zwitterion, or can exist in salt form. Said salt can be any salt of either organic or base addition salts, in particular any pharmaceutically acceptable organic or inorganic addition salt conventionally used in medicine.

  The term “pharmaceutically acceptable salt” refers to a relatively non-toxic inorganic or organic acid addition salt of a compound of the invention. See, for example, S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.

  Suitable pharmaceutically acceptable salts of the compounds of the invention can be, for example, acid addition salts of the compounds of the invention having a nitrogen atom in the chain or ring that are sufficiently basic, such as hydrochloric acid, Inorganic acids such as hydrobromic acid, hydroiodic acid, sulfuric acid, disulfuric acid, phosphoric acid or nitric acid, or formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid , Undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, Nicotinic acid, pamoic acid, pectic acid, persulfate, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, Trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfone, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalene disulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, Oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid ( hemisulfuric acid) or an acid addition salt with an organic acid such as thiocyanic acid.

  In addition, other suitable pharmaceutically acceptable salts of the present invention that are sufficiently acidic include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium, ammonium and physiologically acceptable salts. Salts with organic bases that provide cation such as N-methyl-glucamine, dimethylglucamine, ethyl-glucamine, lysine, dicyclohexylamine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol ), Tris-hydroxy-methyl-aminomethane, aminopropanediol, sovak-base, 1-amino-2,3,4-butanetriol. In addition, basic nitrogen-containing groups are lower alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromide and iodide, dialkyl sulfates such as dimethyl, diethyl and dibutyl sulfate, diamyl sulfate, long It can be quaternized with agents such as chain halides such as decyl, lauryl, myristyl and stearyl chloride, bromides and iodides, aralkyl halides such as benzyl and phenethyl bromide.

  One skilled in the art will further recognize that acid addition salts of the claimed compounds can be prepared by reaction of the compound with a suitable inorganic or organic acid by any of a number of known methods. Alternatively, the alkali metal salts and alkaline earth metal salts of the acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base by various known methods.

  The present invention includes all possible salts of the compounds of the invention as a single salt or as any mixture of the above salts in any ratio.

As used herein, the term “in vivo hydrolysable ester” refers to an in vivo hydrolysable ester of a compound of the invention containing a carboxy or hydroxyl group, eg, human or animal It is understood to mean a pharmaceutically acceptable ester that hydrolyzes in the body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include, for example, alkyl, cycloalkyl and optionally substituted phenylalkyl, especially benzyl esters, C ₁ -C ₆ alkoxymethyl esters, such as methoxymethyl. C ₁ -C ₆ alkanoyloxymethyl esters such as pivaloyloxymethyl, phthalidyl esters, C ₃ -C ₈ cycloalkoxy-carbonyloxy-C ₁ -C ₆ alkyl esters such as 1-cyclohexylcarbonyloxyethyl 1,3-dioxolen-2-onylmethyl esters such as 5-methyl-1,3-dioxolen-2-onylmethyl; and C ₁ -C ₆ -alkoxycarbonyloxyethyl esters such as 1-methoxycarbonyloxy Ethyl, and any carboxy group in the compounds of the present invention It may be made.

  In vivo hydrolyzable esters of the compounds of the invention containing a hydroxyl group include inorganic esters that decompose as a result of in vivo hydrolysis of the ester to provide the parent hydroxy group, such as phosphate esters and α-acyloxyalkyl ethers. As well as related compounds. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. Choices of in vivo hydrolyzable ester-forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to provide alkyl carbonate esters), dialkylcarbamoyl and N- ( Dialkylaminoethyl) -N-alkylcarbamoyl (to provide the carbamate), dialkylaminoacetyl and carboxyacetyl. The present invention covers such esters.

  Furthermore, the present invention includes all possible crystal forms or polymorphs of the compounds of the present invention, including a single polymorph or a mixture of more than one polymorph in any ratio.

According to a second aspect, the present invention relates to the above general formula (I)
[Where:
R ¹ is C ₁ -C ₁₀ - alkyl -, halo -C ₁ -C ₁₀ - alkyl _{-, HO-C 1 -C 10} - alkyl -, C ₁ -C ₁₀ - alkoxy -C ₁ -C ₁₀ - alkyl - Aryloxy-C ₁ -C ₁₀ -alkyl-, halo-C ₁ -C ₁₀ -alkoxy-C ₁ -C ₁₀ -alkyl-, C ₂ -C ₁₀ -alkenyl-, C ₂ -C ₁₀ -alkynyl-, C ₃ -C ₁₀ - cycloalkyl -, 3-to 10-membered heterocycloalkyl -, aryl -, C ₁ -C ₆ - alkylene - aryl -, C ₁ -C ₆ - alkylene - heteroaryl -, - C ₁ -C ₆ - alkylene -C ₃ -C ₁₀ - cycloalkyl, -C ₁ -C ₆ - alkylene - (3-to 10-membered heterocycloalkyl), - C ₁ -C ₆ - alkylene - aryl, -C ₁ A -C ₆ -alkylene-heteroaryl group,
Here, the following substituents optionally above groups: halo -, hydroxy -, cyano -, nitro -, C ₁ -C ₆ - alkyl -, halo -C ₁ -C ₆ - alkyl -, C ₁ -C ₆ -alkoxy-, halo-C ₁ -C ₆ -alkoxy-, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl -, C ₃ -C ₁₀ - cycloalkyl -, 3-to 10-membered heterocycloalkyl -, - C (= O) OH, -C (= O) OC 1 -C 6 - alkyl, -C (= O ) OC ₃ -C ₁₀ -cycloalkyl, -OC (= O) -C ₁ -C ₆ -alkyl, -OC (= O) -C ₃ -C ₁₀ -cycloalkyl, -N (H) C (= O ) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -N (H) S (= O) ₂ R ⁸ , -N (C ₁ -C ₆ -alkyl) S ( = O) ₂ R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -OC (= O) NR ⁹ R ¹⁰ , -N (H) C (= O) OR ⁸ , -N (C ₁ -C ₆ -Alkyl) C (= O) OR ⁸ , -N (H) C (= O) NR ⁹ R ¹⁰ , -N (C ₁ -C ₆ -alkyl) C (= O) NR ⁹ R ¹⁰ , -SR ^{8 , -S (= O) R 8} , -S (= O) 2 R 8, -S (= O) 2 NR 9 R 10, selected from -NR ⁹ R ^10, 1 or more times by identical or different substituents It may be substituted,
R ² is an aryl- or heteroaryl-group,
Wherein the above groups are optionally substituted by the following substituents: halo-, hydroxy-, cyano-, nitro-, C ₁ -C ₆ -alkyl-, halo-C ₁ -C ₆ -alkyl-, HO-C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkoxy-, halo-C ₁ -C ₆ -alkoxy-, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkyl-C (= O) N (H) -C ₁ -C ₆ -alkyl-, C ₃ -C ₁₀ -cycloalkyl-, 3-to 10-membered heterocycloalkyl -, - C (= O) -C 1 -C 6 - alkyl, -C (= O) OH, -C (= O) OC 1 -C 6 - alkyl, -C (= O) OC ₃ -C ₁₀ -cycloalkyl, -OC (= O) -C ₁ -C ₆ -alkyl, -OC (= O) -C ₃ -C ₁₀ -cycloalkyl, -N (H) C (= O) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -N (H) S (= O) ₂ R ⁸ , -N (C ₁ -C ₆ -alkyl ) S (= O) ₂ R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -OC (= O) NR ⁹ R ¹⁰ , -N (H) C (= O) OR ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) OR ⁸ , -N (H) C (= O) NR ⁹ R ¹⁰ , -N (C ₁ -C ₆ -alkyl) C (= O) NR ⁹ R ¹⁰ , -SR ⁸ , -S (= O) R ⁸ , -S (= O) ₂ R ⁸ , -S (= O) ₂ NR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ may be substituted one or more times with the same or different substituents,
R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ are each independently a hydrogen atom, a halogen atom, hydroxy, cyano, nitro, or a group selected from: C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halo-C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkoxy -C ₁ -C ₆ - alkyl, C ₃ -C ₁₀ - cycloalkyl, 3-to 10-membered heterocycloalkyl, -C (= O) OH, -C (= O) OC 1 -C 6 - alkyl, -C (= O) OC ₃ -C ₁₀ -cycloalkyl, -N (H) C (= O) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -N ( H) S (= O) ₂ R ⁸ , -N (C ₁ -C ₆ -alkyl) S (= O) ₂ R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -OC (= O) NR ⁹ R ¹⁰ , -N (H) C (= O) OR ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) OR ⁸ , -N (H) C (= O) NR ⁹ R ¹⁰ , -N (C ₁ -C ₆ -alkyl) C (= O) NR ⁹ R ¹⁰ , -SR ⁸ , -S (= O) R ⁸ , -S (= O) ₂ R ⁸ , -S (= O) ₂ NR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ , C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, aryl, heteroaryl, C ₁ -C ₆ -Alkylene-aryl, C ₁ -C ₆ -alkylene-heteroaryl, -C ₁ -C ₆ -alkylene-C ₃ -C ₁₀ -cycloalkyl or C ₁ -C ₆ -alkylene-3- to 10-membered heterocyclo An alkyl group,
Wherein the above group optionally has the following substituents: halogen, hydroxy, cyano, nitro, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halo- C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl , 3-to 10-membered heterocycloalkyl, -C (= O) OH, -C (= O) OC 1 -C 6 - _{alkyl, -C (= O) OC 3} -C 10 - cycloalkyl, -N (H) C (= O) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -N (H) S (= O) ₂ R ⁸ , -N (C _1- C ₆ -alkyl) S (= O) ₂ R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -OC (= O) NR ⁹ R ¹⁰ , -N (H) C (= O) OR ⁸ ,- N (C ₁ -C ₆ -alkyl) C (= O) OR ⁸ , -N (H) C (= O) NR ⁹ R ¹⁰ , -N (C ₁ -C ₆ -alkyl) C (= O) NR ⁹ R ¹⁰ , -SR ⁸ , -S (= O) R ⁸ , -S (= O) ₂ R ⁸ , -S (= O) ₂ NR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ May be substituted one or more times by different substituents,
R ⁸ , R ⁹ and R ¹⁰ are each independently a hydrogen atom, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, HO-C ₁ -C ₆ -alkyl-, cyano-C ₁ -C ₆ -alkyl-, C ₂ -C ₁₀ -alkynyl-C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkoxy- C ₁ -C ₆ -alkyl, H ₂ NC (= O) -C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkyl-N (H) C (= O) -C ₁ -C ₆ -alkyl _{-, H 2 NS (= O} ) 2 -C 1 -C 6 - alkyl -, C ₂ -C ₆ - alkenyl, C ₂ -C ₆ - alkynyl, C ₃ -C ₁₀ - cycloalkyl, 3-to 10- Membered heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ -alkylene-aryl, -C ₁ -C ₆ -alkylene-heteroaryl, -C ₁ -C ₆ -alkylene-C ₃ -C ₁₀ -cycloalkyl, A -C ₁ -C ₆ -alkylene-3- to 10-membered heterocycloalkyl group,
Where the above C ₃ -C ₁₀ -cycloalkyl group is optionally halogen atom, cyano, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, HO-C ₁ -C ₆ -alkyl May be substituted one or more times by a C ₁ -C ₆ -alkoxy, C ₃ -C ₁₀ -cycloalkyl, aryl or heteroaryl group,
Wherein the above aryl group optionally has the following substituents: halogen, hydroxy, cyano, nitro, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halo -C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cyclo alkyl, 3-to 10-membered heterocycloalkyl, -C ₁ -C ₆ - alkylene -3-to 10-membered heterocycloalkyl, -C (= O) OH, -C (= O) OC 1 -C 6 -Alkyl, -C (= O) OC ₃ -C ₁₀ -cycloalkyl, -N (H) C (= O) -C ₁ -C ₆ -alkyl, -N (H) C (= O) -heteroaryl , -N (C ₁ -C ₆ -alkyl) C (= O) -C ₁ -C ₆ -alkyl, -N (H) S (= O) ₂ -C ₁ -C ₆ -alkyl, -N (C ₁ -C ₆ - _{alkyl) S (= O) 2 -C} 1 -C 6 - _{alkyl, -C (= O) NH 2} , -C (= O) N (H) -C 1 -C 6 - alkyl, -C (= O) N (C ₁ -C ₆ -alkyl) ₂ , -OC (= O) NH ₂ , -OC (= O) N (H) -C ₁ -C ₆ -alkyl, -OC (= O) N (C ₁ -C ₆ -alkyl) ₂ , -N (H) C (= O) OC ₁ -C ₆ -alkyl, -N (C ₁ -C ₆ -alkyl) C (= O) OC ₁ -C ₆ -alkyl, -N (H) C (= O) NH ₂ , -N (H) C (= O) N (H) -C ₁ -C ₆ -alkyl, -N (H) C (= O) N (C ₁ -C ₆ -alkyl) ₂ , -N (C ₁ -C ₆ -alkyl) C (= O) NH ₂ , -N (C ₁ -C ₆ -alkyl) C (= O) N (H) -C ₁ -C ₆ -alkyl, -N (C ₁ -C ₆ -alkyl) C (= O) N (C ₁ -C ₆ -alkyl) ₂ , -SC ₁ -C ₆ -alkyl, -S (= O) -C ₁ -C ₆ -alkyl, -S (= O ) ₂ -C ₁ -C ₆ -alkyl, -S (= O) ₂ NH ₂ , -S (= O) ₂ N (H) -C ₁ -C ₆ -alkyl, -S (= O) ₂ N ( C ₁ -C ₆ -alkyl) ₂ , -NH ₂ , -N (H) -C ₁ -C ₆ -alkyl, -N (C ₁ -C ₆ -alkyl) ₂ May be replaced more than once,
Or R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached are 3- to 10-membered heterocycloalkyl groups;
However,
R ¹ is -CH ₂ CH ₂ CH ₂ OH,
-CH ₂ CH ₂ CH ₂ O (C = O) -R _a ,
-CH ₂ CH ₂ CH ₂ O (C = O) -OR _a ,
-CH ₂ CH ₂ CH ₂ O (C = O) -CHR _a NR _b R _c ,
Where R _a , R _b , R _c are the same or different and are H, C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl, C ₂ -C ₁₀ -alkynyl, phenyl and Selected from the group consisting of heteroaryl]
Or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

According to a third aspect, the present invention provides the above general formula (I)
[Where:
R ¹ is C ₁ -C ₁₀ - alkyl -, halo -C ₁ -C ₁₀ - alkyl _{-, HO-C 1 -C 10} - alkyl -, C ₁ -C ₁₀ - alkoxy -C ₁ -C ₁₀ - alkyl - Aryloxy-C ₁ -C ₁₀ -alkyl-, halo-C ₁ -C ₁₀ -alkoxy-C ₁ -C ₁₀ -alkyl-, C ₂ -C ₁₀ -alkenyl-, C ₂ -C ₁₀ -alkynyl-, C ₃ -C ₁₀ - cycloalkyl -, 3-to 10-membered heterocycloalkyl -, aryl -, C ₁ -C ₆ - alkylene - aryl -, C ₁ -C ₆ - alkylene - heteroaryl -, - C ₁ -C ₆ - alkylene -C ₃ -C ₁₀ - cycloalkyl, -C ₁ -C ₆ - alkylene - (3-to 10-membered heterocycloalkyl), - C ₁ -C ₆ - alkylene - aryl, -C ₁ A -C ₆ -alkylene-heteroaryl group,
Here, the following substituents optionally above groups: halo -, hydroxy -, cyano -, nitro -, C ₁ -C ₆ - alkyl -, halo -C ₁ -C ₆ - alkyl -, C ₁ -C ₆ -alkoxy-, halo-C ₁ -C ₆ -alkoxy-, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl -, C ₃ -C ₁₀ - cycloalkyl -, 3-to 10-membered heterocycloalkyl -, - C (= O) OH, -C (= O) OC 1 -C 6 - alkyl, -C (= O ) OC ₃ -C ₁₀ -cycloalkyl, -OC (= O) -C ₁ -C ₆ -alkyl, -OC (= O) -C ₃ -C ₁₀ -cycloalkyl, -N (H) C (= O ) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -N (H) S (= O) ₂ R ⁸ , -N (C ₁ -C ₆ -alkyl) S ( = O) ₂ R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -OC (= O) NR ⁹ R ¹⁰ , -N (H) C (= O) OR ⁸ , -N (C ₁ -C ₆ -Alkyl) C (= O) OR ⁸ , -N (H) C (= O) NR ⁹ R ¹⁰ , -N (C ₁ -C ₆ -alkyl) C (= O) NR ⁹ R ¹⁰ , -SR ^{8 , -S (= O) R 8} , -S (= O) 2 R 8, -S (= O) 2 NR 9 R 10, selected from -NR ⁹ R ^10, 1 or more times by identical or different substituents It may be substituted,
R ² is an aryl- or heteroaryl-group,
Wherein the above groups optionally have the following substituents: halo-, hydroxy-, cyano-, nitro-, C ₁ -C ₆ -alkyl-, halo-C ₁ -C ₆ -alkyl-, HO-C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkoxy-, halo-C ₁ -C ₆ -alkoxy-, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkyl-C (= O) N (H) -C ₁ -C ₆ -alkyl-, C ₃ -C ₁₀ -cycloalkyl-, 3-to 10-membered heterocycloalkyl -, - C (= O) -C 1 -C 6 - alkyl, -C (= O) OH, -C (= O) OC 1 -C 6 - alkyl, -C (= O) OC ₃ -C ₁₀ -cycloalkyl, -OC (= O) -C ₁ -C ₆ -alkyl, -OC (= O) -C ₃ -C ₁₀ -cycloalkyl, -N (H) C (= O) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -N (H) S (= O) ₂ R ⁸ , -N (C ₁ -C ₆ -alkyl ) S (= O) ₂ R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -OC (= O) NR ⁹ R ¹⁰ , -N (H) C (= O) OR ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) OR ⁸ , -N (H) C (= O) NR ⁹ R ¹⁰ , -N (C ₁ -C ₆ -alkyl) C (= O) NR ⁹ R ¹⁰ , -SR ⁸ , -S (= O) R ⁸ , -S (= O) ₂ R ⁸ , -S (= O) ₂ NR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ may be substituted one or more times with the same or different substituents,
R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently a hydrogen atom, a halogen atom, hydroxy, cyano, nitro or a group selected from the following: C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, -N (H) C (= O) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ and
Wherein the above group optionally has the following substituents: halogen, hydroxy, cyano, nitro, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halo- C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl , 3-to 10-membered heterocycloalkyl, -C (= O) OH, -C (= O) OC 1 -C 6 - _{alkyl, -C (= O) OC 3} -C 10 - cycloalkyl, -N (H) C (= O) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -N (H) S (= O) ₂ R ⁸ , -N (C _1- C ₆ -alkyl) S (= O) ₂ R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -OC (= O) NR ⁹ R ¹⁰ , -N (H) C (= O) OR ⁸ ,- N (C ₁ -C ₆ -alkyl) C (= O) OR ⁸ , -N (H) C (= O) NR ⁹ R ¹⁰ , -N (C ₁ -C ₆ -alkyl) C (= O) NR ⁹ R ¹⁰ , -SR ⁸ , -S (= O) R ⁸ , -S (= O) ₂ R ⁸ , -S (= O) ₂ NR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ May be substituted one or more times by different substituents,
R ⁸ , R ⁹ and R ¹⁰ are each independently a hydrogen atom, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, HO-C ₁ -C ₆ -alkyl-, cyano-C _1- C ₆ -alkyl-, C ₂ -C ₁₀ -alkynyl-C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, H ₂ NC (= O) -C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkyl-N (H) C (= O) -C ₁ -C ₆ -alkyl- _{, H 2 NS (= O)} 2 -C 1 -C 6 - alkyl -, C ₂ -C ₆ - alkenyl, C ₂ -C ₆ - alkynyl, C ₃ -C ₁₀ - cycloalkyl, 3-to 10-membered Heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ -alkylene-aryl, -C ₁ -C ₆ -alkylene-heteroaryl, -C ₁ -C ₆ -alkylene-C ₃ -C ₁₀ -cycloalkyl,- A C ₁ -C ₆ -alkylene-3- to 10-membered heterocycloalkyl group,
Here, the above C ₃ -C ₁₀ -cycloalkyl group may optionally have the following substituents: halogen atom, cyano, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, HO-C _1- May be substituted one or more times by a C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₁₀ -cycloalkyl, aryl or heteroaryl group,
Wherein the above aryl group optionally has the following substituents: halogen, hydroxy, cyano, nitro, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halo -C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cyclo alkyl, 3-to 10-membered heterocycloalkyl, -C ₁ -C ₆ - alkylene -3-to 10-membered heterocycloalkyl, -C (= O) OH, -C (= O) OC 1 -C 6 - _{alkyl, -C (= O) OC 3} -C 10 - cycloalkyl, -N (H) C (= O) -C 1 -C 6 - alkyl, N (H) C (= O) - heteroaryl, N (C ₁ -C ₆ -alkyl) C (= O) -C ₁ -C ₆ -alkyl, -N (H) S (= O) ₂ -C ₁ -C ₆ -alkyl, -N (C _1- C ₆ -alkyl) S (= O) ₂ -C ₁ -C ₆ -alkyl, -C (= O) NH ₂ , -C (= O) N (H) -C ₁ -C ₆ -alkyl, -C (= O) N (C ₁ -C ₆ -alkyl) ₂ , -OC (= O) NH ₂ , -OC (= O) N (H) -C ₁ -C ₆ -alkyl, -OC (= O) N (C ₁ -C ₆ -alkyl) ₂ -N (H) C (= O) OC ₁ -C ₆ -alkyl, -N (C ₁ -C ₆ -alkyl) C (= O) OC ₁ -C ₆ -alkyl, -N (H) C (= O) NH ₂ , -N (H) C (= O) N (H) -C ₁ -C ₆ -alkyl, -N (H) C (= O) N (C ₁ -C ₆ -alkyl) ₂ , -N (C ₁ -C ₆ -alkyl ) C (= O) NH ₂ , -N (C ₁ -C ₆ -alkyl) C (= O) N (H) -C ₁ -C ₆ -alkyl, -N (C ₁ -C ₆ -alkyl) C (= O) N (C ₁ -C ₆ -alkyl) ₂ , -SC ₁ -C ₆ -alkyl, -S (= O) -C ₁ -C ₆ -alkyl, -S (= O) ₂ -C ₁ -C ₆ -alkyl, -S (= O) ₂ NH ₂ , -S (= O) ₂ N (H) -C ₁ -C ₆ -alkyl, -S (= O) ₂ N (C ₁ -C ₆ -Alkyl) ₂ , —NH ₂ , —N (H) —C ₁ -C ₆ -alkyl, —N (C ₁ -C ₆ -alkyl) ₂ , substituted one or more times with the same or different substituents You can,
Or R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached are 3- to 10-membered heterocycloalkyl groups;
However,
R ¹ is -CH ₂ CH ₂ CH ₂ OH,
-CH ₂ CH ₂ CH ₂ O (C = O) -R _a ,
-CH ₂ CH ₂ CH ₂ O (C = O) -OR _a ,
-CH ₂ CH ₂ CH ₂ O (C = O) -CHR _a NR _b R _c ,
R _a , R _b , R _c are the same or different and are from H, C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl, C ₂ -C ₁₀ -alkynyl, phenyl and heteroaryl Selected from the group]
Or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

In a further embodiment of the above aspects, the present invention provides compounds of formula (I)
[Where:
R ¹ is C ₁ -C ₁₀ - alkyl -, halo -C ₁ -C ₁₀ - alkyl _{-, HO-C 1 -C 10} - alkyl -, C ₁ -C ₁₀ - alkoxy -C ₁ -C ₁₀ - alkyl - Aryloxy-C ₁ -C ₁₀ -alkyl-, halo-C ₁ -C ₁₀ -alkoxy-C ₁ -C ₁₀ -alkyl-, C ₂ -C ₁₀ -alkenyl-, C ₂ -C ₁₀ -alkynyl-, C ₃ -C ₁₀ - cycloalkyl -, 3-to 10-membered heterocycloalkyl -, aryl -, heteroaryl -, C ₁ -C ₆ - alkylene - aryl -, C ₁ -C ₆ - alkylene - heteroaryl - , -C ₁ -C ₆ -alkylene-C ₃ -C ₁₀ -cycloalkyl, -C ₁ -C ₆ -alkylene- (3- to 10-membered heterocycloalkyl), -C ₁ -C ₆ -alkylene-aryl A -C ₁ -C ₆ -alkylene-heteroaryl group,
Here, the following substituents optionally above groups: halo -, hydroxy -, cyano -, nitro -, C ₁ -C ₆ - alkyl -, halo -C ₁ -C ₆ - alkyl -, C ₁ -C ₆ -alkoxy-, halo-C ₁ -C ₆ -alkoxy-, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl -, C ₃ -C ₁₀ - cycloalkyl -, 3-to 10-membered heterocycloalkyl -, - C (= O) OH, -C (= O) OC 1 -C 6 - alkyl, -C (= O ) OC ₃ -C ₁₀ -cycloalkyl, -OC (= O) -C ₁ -C ₆ -alkyl, -OC (= O) -C ₃ -C ₁₀ -cycloalkyl, -N (H) C (= O ) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -N (H) S (= O) ₂ R ⁸ , -N (C ₁ -C ₆ -alkyl) S ( = O) ₂ R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -OC (= O) NR ⁹ R ¹⁰ , -N (H) C (= O) OR ⁸ , -N (C ₁ -C ₆ -Alkyl) C (= O) OR ⁸ , -N (H) C (= O) NR ⁹ R ¹⁰ , -N (C ₁ -C ₆ -alkyl) C (= O) NR ⁹ R ¹⁰ , -SR ^{8 , -S (= O) R 8} , -S (= O) 2 R 8, -S (= O) 2 NR 9 R 10, selected from -NR ⁹ R ^10, 1 or more times by identical or different substituents May be substituted]
Of the compound.

In a further embodiment of the above aspects, the present invention provides compounds of formula (I)
[Where:
R ² is -CN, -NR ⁹ R ¹⁰ , -OR ⁹ , C ₂ -C ₁₀ -alkenyl-, C ₂ -C ₁₀ -alkynyl-, aryl-, heteroaryl-, C ₁ -C ₆ -alkylene-aryl -, A C ₁ -C ₆ -alkylene-heteroaryl-group,
Wherein the above groups are optionally substituted by the following substituents: halo-, hydroxy-, cyano-, nitro-, C ₁ -C ₆ -alkyl-, halo-C ₁ -C ₆ -alkyl-, HO-C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkoxy-, halo-C ₁ -C ₆ -alkoxy-, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkyl-C (= O) N (H) -C ₁ -C ₆ -alkyl-, C ₃ -C ₁₀ -cycloalkyl-, 3-to 10-membered heterocycloalkyl -, - C (= O) -C 1 -C 6 - alkyl, -C (= O) OH, -C (= O) OC 1 -C 6 - alkyl, -C (= O) OC ₃ -C ₁₀ -cycloalkyl, -OC (= O) -C ₁ -C ₆ -alkyl, -OC (= O) -C ₃ -C ₁₀ -cycloalkyl, -N (H) C (= O) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -N (H) S (= O) ₂ R ⁸ , -N (C ₁ -C ₆ -alkyl ) S (= O) ₂ R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -OC (= O) NR ⁹ R ¹⁰ , -N (H) C (= O) OR ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) OR ⁸ , -N (H) C (= O) NR ⁹ R ¹⁰ , -N (C ₁ -C ₆ -alkyl) C (= O) NR ⁹ R ¹⁰ , -SR ⁸ , -S (= O) R ⁸ , -S (= O) ₂ R ⁸ , -S (= O) ₂ NR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ may be substituted one or more times with the same or different substituents]
Of the compound.

In a further embodiment of the above aspects, the present invention provides compounds of formula (I)
[Where:
R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ are each independently a hydrogen atom, a halogen atom, hydroxy, cyano, nitro or a group selected from: C ₁ -C ₆ -alkyl, halo-C _1- C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halo-C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl, 3- to ₁₀ -membered heterocycloalkyl, -C (= O) OH, -C (= O) OC ₁ -C ₆ -alkyl, -C (= O) OC ₃ -C ₁₀ -cycloalkyl, -N (H) C (= O) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -N (H) S (= O) ₂ R ⁸ , -N (C ₁ -C ₆ -alkyl) S (= O) ₂ R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -OC (= O) NR ⁹ R ¹⁰ , -N (H) C (= O) OR ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) OR ⁸ , -N (H) C (= O) NR ⁹ R ¹⁰ , -N (C ₁ -C ₆ -alkyl) C (= O) NR ⁹ R ¹⁰ , -SR ⁸ , -S (= O) R ⁸ , -S (= O) ₂ R ⁸ , -S (= O) ₂ NR ^{9 R 10, -NR 9 R 10} , C 2 -C 6 - alkenyl, C ₂ -C ₆ - alkynyl, aryl, heteroaryl, C ₁ -C ₆ - A Killen - aryl, C ₁ -C ₆ - alkylene - heteroaryl, -C ₁ -C ₆ - alkylene -C ₃ -C ₁₀ - cycloalkyl or C ₁ -C ₆ - alkylene -3-to 10-membered heterocycloalkyl Group,
Wherein the above groups optionally have the following substituents: halogen, hydroxy, cyano, nitro, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halo- C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl , 3-to 10-membered heterocycloalkyl, -C (= O) OH, -C (= O) OC 1 -C 6 - _{alkyl, -C (= O) OC 3} -C 10 - cycloalkyl, -N (H) C (= O) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -N (H) S (= O) ₂ R ⁸ , -N (C _1- C ₆ -alkyl) S (= O) ₂ R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -OC (= O) NR ⁹ R ¹⁰ , -N (H) C (= O) OR ⁸ ,- N (C ₁ -C ₆ -alkyl) C (= O) OR ⁸ , -N (H) C (= O) NR ⁹ R ¹⁰ , -N (C ₁ -C ₆ -alkyl) C (= O) NR ⁹ R ¹⁰ , -SR ⁸ , -S (= O) R ⁸ , -S (= O) ₂ R ⁸ , -S (= O) ₂ NR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ May be substituted one or more times by different substituents]
Of the compound.

In a further embodiment of the above aspects, the present invention provides compounds of formula (I)
[Where:
R ⁸ , R ⁹ and R ¹⁰ are each independently a hydrogen atom, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, HO-C ₁ -C ₆ -alkyl-, cyano-C _1- C ₆ -alkyl-, C ₂ -C ₁₀ -alkynyl-C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, H ₂ NC (= O) -C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkyl-N (H) C (= O) -C ₁ -C ₆ -alkyl- _{, H 2 NS (= O)} 2 -C 1 -C 6 - alkyl -, C ₂ -C ₆ - alkenyl, C ₂ -C ₆ - alkynyl, C ₃ -C ₁₀ - cycloalkyl, 3-to 10-membered Heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ -alkylene-aryl, -C ₁ -C ₆ -alkylene-heteroaryl, -C ₁ -C ₆ -alkylene-C ₃ -C ₁₀ -cycloalkyl,- A C ₁ -C ₆ -alkylene-3- to 10-membered heterocycloalkyl group,
Where the above C ₃ -C ₁₀ -cycloalkyl group is optionally halogen atom, cyano, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, HO-C ₁ -C ₆ -alkyl May be substituted one or more times by a C ₁ -C ₆ -alkoxy, C ₃ -C ₁₀ -cycloalkyl, aryl or heteroaryl group,
Wherein the above aryl group optionally has the following substituents: halogen, hydroxy, cyano, nitro, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, Halo-C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, C ₃ -C _10- cycloalkyl, 3-to 10-membered heterocycloalkyl, -C ₁ -C ₆ - alkylene -3-to 10-membered heterocycloalkyl, -C (= O) OH, -C (= O) OC 1 -C ₆ -alkyl, -C (= O) OC ₃ -C ₁₀ -cycloalkyl, -N (H) C (= O) -C ₁ -C ₆ -alkyl, -N (H) C (= O) -hetero Aryl, -N (C ₁ -C ₆ -alkyl) C (= O) -C ₁ -C ₆ -alkyl, -N (H) S (= O) ₂ -C ₁ -C ₆ -alkyl, -N ( C ₁ -C ₆ -alkyl) S (= O) ₂ -C ₁ -C ₆ -alkyl, -C (= O) NH ₂ , -C (= O) N (H) -C ₁ -C ₆ -alkyl , -C (= O) N (C ₁ -C ₆ -alkyl) ₂ , -OC (= O) NH ₂ , -OC (= O) N (H) -C ₁ -C ₆ -alkyl, -OC ( = O) N (C ₁ -C ₆ -alkyl) ₂ , -N (H) C (= O) OC ₁ -C ₆ -alkyl, -N (C ₁ -C ₆ -alkyl) C (= O) OC ₁ -C ₆ -alkyl, -N (H) C (= O) NH ₂ , -N (H) C (= O) N (H) -C ₁ -C ₆ -alkyl, -N (H) C (= O) N (C ₁ -C ₆ -alkyl) ₂ , -N (C ₁ -C ₆ -alkyl) C (= O) NH ₂ , -N (C ₁ -C ₆ -alkyl) C (= O) N (H) -C ₁ -C ₆ -alkyl, -N (C ₁ -C ₆ -alkyl) C (= O) N (C ₁ -C ₆ -alkyl) ₂ , -SC ₁ -C ₆ -alkyl, -S (= O) -C ₁ -C ₆ -alkyl, -S (= O) ₂ -C ₁ -C ₆ -alkyl, -S (= O) ₂ NH ₂ , -S (= O) ₂ N (H) -C ₁ -C ₆ -alkyl, -S (= O) ₂ N (C ₁ -C ₆ -alkyl) ₂ , -NH ₂ , -N (H) -C ₁ -C ₆ -alkyl, -N (C ₁ -C ₆ -alkyl) ₂ , the same or different May be substituted one or more times by a substituent,
Or
R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached are 3- to 10-membered heterocycloalkyl groups;
However,
R ¹ is -CH ₂ CH ₂ CH ₂ OH,
-CH ₂ CH ₂ CH ₂ O (C = O) -R _a ,
-CH ₂ CH ₂ CH ₂ O (C = O) -OR _a ,
-CH ₂ CH ₂ CH ₂ O (C = O) -CHR _a NR _b R _c ,
R _a , R _b , R _c are the same or different and are from H, C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl, C ₂ -C ₁₀ -alkynyl, phenyl and heteroaryl Selected from the group]
Of the compound.

In a further embodiment of the above aspects, the present invention provides compounds of formula (I)
[Where:
R ² is an aryl- or heteroaryl-group,
Wherein the above groups are optionally substituted by the following substituents: halo-, hydroxy-, cyano-, nitro-, C ₁ -C ₆ -alkyl-, halo-C ₁ -C ₆ -alkyl-, HO-C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkoxy-, halo-C ₁ -C ₆ -alkoxy-, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkyl-C (= O) N (H) -C ₁ -C ₆ -alkyl-, C ₃ -C ₁₀ -cycloalkyl, 3 -～10- membered _{heterocycloalkyl, -C (= O) -C 1} -C 6 - alkyl, -C (= O) OH, -C (= O) OC 1 -C 6 - alkyl, -C (= O) OC ₃ -C ₁₀ -cycloalkyl, -OC (= O) -C ₁ -C ₆ -alkyl, -OC (= O) -C ₃ -C ₁₀ -cycloalkyl, -N (H) C (= O) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -N (H) S (= O) ₂ R ⁸ , -N (C ₁ -C ₆ -alkyl) S (= O) ₂ R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -OC (= O) NR ⁹ R ¹⁰ , -N (H) C (= O) OR ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) OR ⁸ , -N (H) C (= O) NR ⁹ R ¹⁰ , -N (C ₁ -C ₆ -alkyl) C (= O) NR ⁹ R ¹⁰ , -SR ⁸ , -S (= O) R ⁸ ,- S (= O) ₂ R ⁸ , —S (═O) ₂ NR ⁹ R ¹⁰ , —NR ⁹ R ¹⁰ may be substituted one or more times with the same or different substituents]
Of the compound.

In a further embodiment of the above aspects, the present invention provides compounds of formula (I)
[Where:
R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ are each independently a hydrogen atom, a halogen atom, hydroxy, cyano, nitro or a group selected from: C ₁ -C ₆ -alkyl, halo-C _1- C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halo-C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl, 3- to ₁₀ -membered heterocycloalkyl, -C (= O) OH, -C (= O) OC ₁ -C ₆ -alkyl, -C (= O) OC ₃ -C ₁₀ -cycloalkyl, -N (H) C (= O) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -N (H) S (= O) ₂ R ⁸ , -N (C ₁ -C ₆ -alkyl) S (= O) ₂ R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -OC (= O) NR ⁹ R ¹⁰ , -N (H) C (= O) OR ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) OR ⁸ , -N (H) C (= O) NR ⁹ R ¹⁰ , -N (C ₁ -C ₆ -alkyl) C (= O) NR ⁹ R ¹⁰ , -SR ⁸ , -S (= O) R ⁸ , -S (= O) ₂ R ⁸ , -S (= O) ₂ NR ^{9 R 10, -NR 9 R 10} , C 2 -C 6 - alkenyl, C ₂ -C ₆ - alkynyl, aryl, heteroaryl, C ₁ -C ₆ - A Killen - aryl, C ₁ -C ₆ - alkylene - heteroaryl, -C ₁ -C ₆ - alkylene -C ₃ -C ₁₀ - cycloalkyl or C ₁ -C ₆ - alkylene -3-to 10-membered heterocycloalkyl Group,
Wherein the above group optionally has the following substituents: halogen, hydroxy, cyano, nitro, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halo- C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl , 3-to 10-membered heterocycloalkyl, -C (= O) OH, -C (= O) OC 1 -C 6 - _{alkyl, -C (= O) OC 3} -C 10 - cycloalkyl, -N (H) C (= O) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -N (H) S (= O) ₂ R ⁸ , -N (C _1- C ₆ -alkyl) S (= O) ₂ R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -OC (= O) NR ⁹ R ¹⁰ , -N (H) C (= O) OR ⁸ ,- N (C ₁ -C ₆ -alkyl) C (= O) OR ⁸ , -N (H) C (= O) NR ⁹ R ¹⁰ , -N (C ₁ -C ₆ -alkyl) C (= O) NR ⁹ R ¹⁰ , -SR ⁸ , -S (= O) R ⁸ , -S (= O) ₂ R ⁸ , -S (= O) ₂ NR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ May be substituted one or more times by different substituents]
Of the compound.

In a further embodiment of the above aspects, the present invention provides compounds of formula (I)
[Where:
R ⁸ , R ⁹ and R ¹⁰ are each independently a hydrogen atom, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, HO-C ₁ -C ₆ -alkyl-, cyano-C ₁ -C ₆ - alkyl -, C ₂ -C ₁₀ - alkynyl -C ₁ -C ₆ - alkyl -, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl, halo -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ -alkyl, H ₂ NC (= O) -C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkyl-N (H) C (= O) -C ₁ -C ₆ -alkyl-, _{H 2 NS (= O) 2} -C 1 -C 6 - alkyl -, C ₂ -C ₆ - alkenyl, C ₂ -C ₆ - alkynyl, C ₃ -C ₁₀ - cycloalkyl, 3-to 10-membered heteroaryl Cycloalkyl, aryl, heteroaryl, C ₁ -C ₆ -alkylene-aryl, -C ₁ -C ₆ -alkylene-heteroaryl, -C ₁ -C ₆ -alkylene-C ₃ -C ₁₀ -cycloalkyl, -C ₁ -C ₆ -alkylene-3- to 10-membered heterocycloalkyl group,
Where the above C ₃ -C ₁₀ -cycloalkyl group is optionally halogen atom, cyano, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, HO-C ₁ -C ₆ -alkyl May be substituted one or more times by a C ₁ -C ₆ -alkoxy, C ₃ -C ₁₀ -cycloalkyl, aryl or heteroaryl group,
Wherein the above aryl group optionally has the following substituents: halogen, hydroxy, cyano, nitro, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halo -C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cyclo alkyl, 3-to 10-membered heterocycloalkyl, -C ₁ -C ₆ - alkylene -3-to 10-membered heterocycloalkyl, -C (= O) OH, -C (= O) OC 1 -C 6 -Alkyl, -C (= O) OC ₃ -C ₁₀ -cycloalkyl, -N (H) C (= O) -C ₁ -C ₆ -alkyl, -N (H) C (= O) -heteroaryl , -N (C ₁ -C ₆ -alkyl) C (= O) -C ₁ -C ₆ -alkyl, -N (H) S (= O) ₂ -C ₁ -C ₆ -alkyl, -N (C ₁ -C ₆ - _{alkyl) S (= O) 2 -C} 1 -C 6 - _{alkyl, -C (= O) NH 2} , -C (= O) N (H) -C 1 -C 6 - alkyl, -C (= O) N (C ₁ -C ₆ -alkyl) ₂ , -OC (= O) NH ₂ , -OC (= O) N (H) -C ₁ -C ₆ -alkyl, -OC (= O) N (C ₁ -C ₆ -alkyl) ₂ , -N (H) C (= O) OC ₁ -C ₆ -alkyl, -N (C ₁ -C ₆ -alkyl) C (= O) OC ₁ -C ₆ -alkyl, -N (H) C (= O) NH ₂ , -N (H) C (= O) N (H) -C ₁ -C ₆ -alkyl, -N (H) C (= O) N (C ₁ -C ₆ -alkyl) ₂ , -N (C ₁ -C ₆ -alkyl) C (= O) NH ₂ , -N (C ₁ -C ₆ -alkyl) C (= O) N (H) -C ₁ -C ₆ -alkyl, -N (C ₁ -C ₆ -alkyl) C (= O) N (C ₁ -C ₆ -alkyl) ₂ , -SC ₁ -C ₆ -alkyl, -S (= O) -C ₁ -C ₆ -alkyl, -S (= O ) ₂ -C ₁ -C ₆ -alkyl, -S (= O) ₂ NH ₂ , -S (= O) ₂ N (H) -C ₁ -C ₆ -alkyl, -S (= O) ₂ N ( C ₁ -C ₆ -alkyl) ₂ , -NH ₂ , -N (H) -C ₁ -C ₆ -alkyl, -N (C ₁ -C ₆ -alkyl) ₂ May be replaced more than once,
Or R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached are 3- to 10-membered heterocycloalkyl groups;
However,
R ¹ is -CH ₂ CH ₂ CH ₂ OH,
-CH ₂ CH ₂ CH ₂ O (C = O) -R _a ,
-CH ₂ CH ₂ CH ₂ O (C = O) -OR _a ,
-CH ₂ CH ₂ CH ₂ O (C = O) -CHR _a NR _b R _c ,
Where R _a , R _b , R _c are the same or different and are H, C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl, C ₂ -C ₁₀ -alkynyl, phenyl and Selected from the group consisting of heteroaryl]
Of the compound.

In a further embodiment of the above aspects, the present invention provides compounds of formula (I)
[Where:
R ¹ is C ₁ -C ₁₀ - alkyl -, halo -C ₁ -C ₁₀ - alkyl _{-, HO-C 1 -C 10} - alkyl -, C ₁ -C ₁₀ - alkoxy -C ₁ -C ₁₀ - alkyl - Aryloxy-C ₁ -C ₁₀ -alkyl-, halo-C ₁ -C ₁₀ -alkoxy-C ₁ -C ₁₀ -alkyl-, C ₂ -C ₁₀ -alkenyl-, C ₂ -C ₁₀ -alkynyl-, C ₃ -C ₁₀ - cycloalkyl -, 3-to 10-membered heterocycloalkyl -, aryl -, C ₁ -C ₆ - alkylene - aryl -, C ₁ -C ₆ - alkylene - heteroaryl -, - C ₁ -C ₆ - alkylene -C ₃ -C ₁₀ - cycloalkyl, -C ₁ -C ₆ - alkylene - (3-to 10-membered heterocycloalkyl), - C ₁ -C ₆ - alkylene - aryl, -C ₁ A -C ₆ -alkylene-heteroaryl group,
Here, the following substituents optionally above groups: halo -, hydroxy -, cyano -, nitro -, C ₁ -C ₆ - alkyl -, halo -C ₁ -C ₆ - alkyl -, C ₁ -C ₆ -alkoxy-, halo-C ₁ -C ₆ -alkoxy-, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl -, C ₃ -C ₁₀ - cycloalkyl, 3-to 10-membered heterocycloalkyl, -C (= O) OH, -C (= O) OC 1 -C 6 - alkyl, -C (= O) OC _3- C ₁₀ -cycloalkyl, -OC (= O) -C ₁ -C ₆ -alkyl, -OC (= O) -C ₃ -C ₁₀ -cycloalkyl, -N (H) C (= O) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -N (H) S (= O) ₂ R ⁸ , -N (C ₁ -C ₆ -alkyl) S (= O ) ₂ R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -OC (= O) NR ⁹ R ¹⁰ , -N (H) C (= O) OR ⁸ , -N (C ₁ -C ₆ -alkyl ) C (= O) OR ⁸ , -N (H) C (= O) NR ⁹ R ¹⁰ , -N (C ₁ -C ₆ -alkyl) C (= O) NR ⁹ R ¹⁰ , -SR ⁸ ,- S (= O) R ⁸ , -S (= O) ₂ R ⁸ , -S (= O) ₂ NR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ or more once with the same or different substituents May be replaced]
Of the compound.

In a further embodiment of the above aspects, the present invention provides compounds of formula (I)
[Where:
R ² is an aryl- or heteroaryl-group,
Wherein the above groups are optionally substituted by the following substituents: halo-, hydroxy-, cyano-, nitro-, C ₁ -C ₆ -alkyl-, halo-C ₁ -C ₆ -alkyl-, HO-C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkoxy-, halo-C ₁ -C ₆ -alkoxy-, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkyl-C (= O) N (H) -C ₁ -C ₆ -alkyl-, C ₃ -C ₁₀ -cycloalkyl-, 3-to 10-membered heterocycloalkyl -, - C (= O) -C 1 -C 6 - alkyl, -C (= O) OH, -C (= O) OC 1 -C 6 - alkyl, -C (= O) OC ₃ -C ₁₀ -cycloalkyl, -OC (= O) -C ₁ -C ₆ -alkyl, -OC (= O) -C ₃ -C ₁₀ -cycloalkyl, -N (H) C (= O) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -N (H) S (= O) ₂ R ⁸ , -N (C ₁ -C ₆ -alkyl ) S (= O) ₂ R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -OC (= O) NR ⁹ R ¹⁰ , -N (H) C (= O) OR ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) OR ⁸ , -N (H) C (= O) NR ⁹ R ¹⁰ , -N (C ₁ -C ₆ -alkyl) C (= O) NR ⁹ R ¹⁰ , -SR ⁸ , -S (= O) R ⁸ , -S (= O) ₂ R ⁸ , -S (= O) ₂ NR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ may be substituted one or more times with the same or different substituents]
Of the compound.

In a further embodiment of the above aspects, the present invention provides compounds of formula (I)
[Where:
R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently a hydrogen atom, a halogen atom, hydroxy, cyano, nitro or a group selected from: C ₁ -C ₆ -alkyl, C ₁ -C ₆ -Alkoxy, -N (H) C (= O) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ and
Wherein the above group optionally has the following substituents: halogen, hydroxy, cyano, nitro, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halo- C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl , 3-to 10-membered heterocycloalkyl, -C (= O) OH, -C (= O) OC 1 -C 6 - _{alkyl, -C (= O) OC 3} -C 10 - cycloalkyl, -N (H) C (= O) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -N (H) S (= O) ₂ R ⁸ , -N (C _1- C ₆ -alkyl) S (= O) ₂ R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -OC (= O) NR ⁹ R ¹⁰ , -N (H) C (= O) OR ⁸ ,- N (C ₁ -C ₆ -alkyl) C (= O) OR ⁸ , -N (H) C (= O) NR ⁹ R ¹⁰ , -N (C ₁ -C ₆ -alkyl) C (= O) NR ⁹ R ¹⁰ , -SR ⁸ , -S (= O) R ⁸ , -S (= O) ₂ R ⁸ , -S (= O) ₂ NR ⁹ R ¹⁰ , -NR ⁹ R ¹⁰ May be substituted one or more times by different substituents]
Of the compound.

In a further embodiment of the above aspects, the present invention provides compounds of formula (I)
[Where:
R ⁸ , R ⁹ and R ¹⁰ are each independently a hydrogen atom, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, HO-C ₁ -C ₆ -alkyl-, cyano-C _1- C ₆ -alkyl-, C ₂ -C ₁₀ -alkynyl-C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, H ₂ NC (= O) -C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkyl-N (H) C (= O) -C ₁ -C ₆ -alkyl- _{, H 2 NS (= O)} 2 -C 1 -C 6 - alkyl -, C ₂ -C ₆ - alkenyl, C ₂ -C ₆ - alkynyl, C ₃ -C ₁₀ - cycloalkyl, 3-to 10-membered Heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ -alkylene-aryl, -C ₁ -C ₆ -alkylene-heteroaryl, -C ₁ -C ₆ -alkylene-C ₃ -C ₁₀ -cycloalkyl,- A C ₁ -C ₆ -alkylene-3- to 10-membered heterocycloalkyl group,
Where the above C ₃ -C ₁₀ -cycloalkyl group is optionally halogen atom, cyano, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, HO-C ₁ -C ₆ -alkyl May be substituted one or more times by a C ₁ -C ₆ -alkoxy, C ₃ -C ₁₀ -cycloalkyl, aryl or heteroaryl group,
Wherein the above aryl group optionally has the following substituents: halogen, hydroxy, cyano, nitro, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halo -C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cyclo alkyl, 3-to 10-membered heterocycloalkyl, -C ₁ -C ₆ - alkylene -3-to 10-membered heterocycloalkyl group, -C (= O) OH, -C (= O) OC 1 -C ₆ -alkyl, -C (= O) OC ₃ -C ₁₀ -cycloalkyl, -N (H) C (= O) -C ₁ -C ₆ -alkyl, -N (H) C (= O) -hetero Aryl, -N (C ₁ -C ₆ -alkyl) C (= O) -C ₁ -C ₆ -alkyl, -N (H) S (= O) ₂ -C ₁ -C ₆ -alkyl, -N ( C ₁ -C ₆ -alkyl) S (= O) ₂ -C ₁ -C ₆ -alkyl, -C (= O) NH ₂ , -C (= O) N (H) -C ₁ -C ₆ -alkyl , -C (= O) N (C ₁ -C ₆ -alkyl) ₂ , -OC (= O) NH ₂ , -OC (= O) N (H) -C ₁ -C ₆ -alkyl, -OC ( = O) N (C ₁ -C ₆ -alkyl) ₂ , -N (H) C (= O) OC ₁ -C ₆ -alkyl, -N (C ₁ -C ₆ -alkyl) C (= O) OC ₁ -C ₆ -alkyl, -N (H) C (= O) NH ₂ , -N (H) C (= O) N (H) -C ₁ -C ₆ -alkyl, -N (H) C (= O) N (C ₁ -C ₆ -alkyl) ₂ , -N (C ₁ -C ₆ -alkyl) C (= O) NH ₂ , -N (C ₁ -C ₆ -alkyl) C (= O) N (H) -C ₁ -C ₆ -alkyl, -N (C ₁ -C ₆ -alkyl) C (= O) N (C ₁ -C ₆ -alkyl) ₂ , -SC ₁ -C ₆ -alkyl, -S (= O) -C ₁ -C ₆ -alkyl, -S (= O ) ₂ -C ₁ -C ₆ -alkyl, -S (= O) ₂ NH ₂ , -S (= O) ₂ N (H) -C ₁ -C ₆ -alkyl, -S (= O) ₂ N ( C ₁ -C ₆ -alkyl) ₂ , -NH ₂ , -N (H) -C ₁ -C ₆ -alkyl, -N (C ₁ -C ₆ -alkyl) ₂ May be substituted one or more times, or
R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached are 3- to 10-membered heterocycloalkyl groups;
However,
R ¹ is -CH ₂ CH ₂ CH ₂ OH,
-CH ₂ CH ₂ CH ₂ O (C = O) -R _a ,
-CH ₂ CH ₂ CH ₂ O (C = O) -OR _a ,
-CH ₂ CH ₂ CH ₂ O (C = O) -CHR _a NR _b R _c ,
Where R _a , R _b , R _c are the same or different and are H, C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl, C ₂ -C ₁₀ -alkynyl, phenyl and Selected from the group consisting of heteroaryl]
Of the compound.

In a further embodiment of the above aspects, the present invention provides compounds of formula (I)
[Where:
R ¹ is C ₁ -C ₁₀ - alkyl -, halo -C ₁ -C ₁₀ - alkyl _{-, HO-C 1 -C 10} - alkyl -, C ₁ -C ₁₀ - alkoxy -C ₁ -C ₁₀ - alkyl - Aryloxy-C ₁ -C ₁₀ -alkyl-, halo-C ₁ -C ₁₀ -alkoxy-C ₁ -C ₁₀ -alkyl-, -C ₁ -C ₆ -alkylene-C ₃ -C ₁₀ -cycloalkyl Yes,
Wherein the above groups are optionally substituted by the following substituents: halo-, hydroxyl-, C ₁ -C ₆ -alkyl-, halo-C ₁ -C ₆ -alkyl-, C ₁ -C ₆ -alkoxy-, halo -C ₁ -C ₆ -alkoxy-, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-, C ₃ -C _And may be substituted one or more times by the same or different substituents selected from ₁₀ -cycloalkyl-, 3- to ₁₀ -membered heterocycloalkyl-]
Of the compound.

In a further embodiment of the above aspects, the present invention provides compounds of formula (I)
[Where:
R ² is an aryl- or heteroaryl- group, said group is substituted once by —C (═O) NR ⁹ R ¹⁰ , and optionally halo-, hydroxy-, cyano-, C ₁ -C ₆ - alkyl -, halo -C ₁ -C ₆ - alkyl - may be substituted with a substituent selected from '
Of the compound.

In a further embodiment of the above aspects, the present invention provides compounds of formula (I)
[Wherein R ² is an aryl- or heteroaryl- group, the above group is substituted once by —C (═O) NH-cyclopropyl, and optionally halo-, hydroxy-, cyano -, C ₁ -C ₆ - alkyl -, halo -C ₁ -C ₆ - may be substituted with a substituent selected from - alkyl
Of the compound.

In a further embodiment of the above aspects, the invention relates to a compound of formula (I), wherein R ⁷ is a hydrogen atom.

  The invention is understood to relate to any sub-combination of any embodiment of the invention of general formula (I) above.

  Even more specifically, the present invention covers compounds of formula (I) disclosed in the Examples section below.

  According to another aspect, the present invention covers a process for the preparation of the compounds of the present invention comprising the steps described herein.

  According to a further aspect, the present invention covers intermediate compounds that are useful for the preparation of the compounds of the invention of general formula (I), in particular in the processes described herein. In particular, the present invention provides a general formula (4)

[Where:
R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined for the compound of general formula (I) in the claims, and Y is a halogen atom]
These compounds are covered.

  According to yet another aspect, the present invention covers the use of the intermediate compound of general formula (4) above for the preparation of the compound of the present invention of general formula (I) above.

Experimental Part As mentioned above, another aspect of the present invention is a method that can be used to produce the compounds according to the present invention.

  The following table shows the abbreviations used in this paragraph and the examples section. The shape of the NMR peak was noted as it appeared in the spectrum and the higher order effects possible were not considered.

The following schemes and procedures show general synthetic routes to compounds of general formula (I) of the present invention, and the schemes and procedures are not intended to be limiting. It will be apparent to those skilled in the art that the order of transformations illustrated in the scheme can be changed in various ways. The order of transformations illustrated in the scheme is therefore not intended to be limiting. Furthermore, the interconversion of any substituents R ¹ , R ² , R ^2a , R ³ , R ⁴ , R ⁵ , R ⁶ or R ⁷ can be performed before and / or after the exemplary conversion. These changes can be the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to those skilled in the art. These transformations include transformations that introduce functional groups that allow further interconversion of substituents. Suitable protecting groups and their introduction and cleavage are well known to those skilled in the art (see, for example, TW Greene and PGM Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999). Specific examples are described in subsequent paragraphs. Furthermore, the continuous process can be performed without post-processing between two or more continuous processes. For example, a “one-pot” reaction can be performed as is well known to those skilled in the art.

The first reaction scheme is shown below.
Synthesis of compounds of general formula (I) Scheme 1

[Where:
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ have the meanings given for general formula (I) above and Y is a halogen atom as defined above. , Z is "suitable functional group", R ² of R ² -Z compound through which is coupled on the carbon atom bearing Y compounds by coupling reaction (4), whereby the Y can be substituted with an R ² group. ]

R ^2a has the same definition as R ² .

Compounds of general formula (I) can be synthesized according to the procedure shown in Scheme 1.
The 2-amino-3-chloroquinoxaline intermediate of general formula (1) is commercially available or can be synthesized according to Scheme 2.

Synthesis of 2-amino-3-chloroquinoxaline intermediate Scheme 2

Those skilled in the art also have many precedent methods for synthesizing suitable 2-amino-3-chloroquinoxaline intermediates of general formula (1), including several 2-amino-3-chloroquinoxaline intermediates. Will recognize that it is commercially available. One possible route to the 2-amino-3-chloroquinoxaline intermediate as shown in Scheme 2 is the commercially available appropriately substituted ortho-amino-aniline (A) corresponding to the corresponding 1,4-dihydro-quinoxaline- Conversion to the 2,3-dione intermediate (B) by condensation with diethyl oxalate. Chlorination of this intermediate (B) with POCl ₃ yields 2,3-dichloro-quinoxaline (C) [eg, the preparation of 2,3-dichloro-fluoroquinoxaline; Ceccarelli et al. / Eur. J. Med Chem. 33 (1998) 943-955]. Aminolysis of the 2,3-dichloro-quinoxaline intermediate yields the required 2-amino-3-chloroquinoxaline intermediate (1). One skilled in the art will recognize that the substitution pattern of the 2,3-dichloro-quinoxaline intermediate can produce regioisomers that must be separated by known methods such as flash chromatography.

With respect to Scheme 1, a suitably substituted 2-amino-3-chloroquinoxaline intermediate of general formula (1) can be obtained in a suitable solvent system, such as THF and water, at temperatures ranging from room temperature to the boiling point of the solvent. -Halo-keto derivatives, for example by reaction with 2-bromo-1,1-diethoxy-ethane, are converted into the corresponding 4-chloro-imidazo [1,2-a] quinoxalines of general formula (2) [See, for example, S. Parra et al./European Journal of Medicinal Chemistry 36 (2001) 255-264]. One skilled in the art will recognize that the substitution pattern of the 2-amino-3-chloroquinoxaline intermediate can produce regioisomers that must be separated by known methods such as flash chromatography.

  The intermediate of general formula (2) is obtained by reaction with a suitable halogenating agent such as NBS in the presence of a suitable solvent such as NMP at a temperature ranging from room temperature to the boiling point of the solvent, preferably at room temperature. It can be converted to the 1-halo-4-chloro-imidazo [1,2-a] quinoxaline intermediate of (3).

  The intermediate of general formula (3) is reacted with a suitable amine in the presence of a suitable base such as DIPEA in a suitable solvent such as DMF or NMP at temperatures ranging from room temperature to the boiling point of the solvent. Can be converted to a substituted 2-amino-7-halo-quinoxaline intermediate (4) [see, eg, C. Deleuze-Masque´fa et al./Bioorg. Med. Chem. 12 (2004) 1129-1139]. I want to]

As shown in Scheme 1 above, the substituted 2-amino-7-halo-quinoxaline intermediate (4) is, for example, a compound of formula R ² —Z, wherein R ² is a compound of general formula (I) above are as defined with respect to, Z is "suitable functional group", via whose functional groups are the R ² group of R ² -Z compound is coupled onto the carbon bearing the Y of the formula (4), It can be directly converted to a compound of general formula (I) by a coupling reaction by replacing Y with the above R ² group, eg a metal catalyzed coupling reaction. Examples of such “suitable functional groups”, Z in R ² -Z include, for example, boronic acids, R ² -B (OH) ₂ , or boronic esters, R ² -B (OC ₁ -C ₆ -Alkyl) ₂ . Or, in such a coupling, Z in R ² -Z can be, for example, amine RNH (R ² = RN), phenol ROH (R ² = RO), alkyne RC≡CH (R2 = RC≡C), It can be an activated hydrogen atom of the alkene RC = CH (R2 = RC = C) or it can be a metal ion, for example Zn ²⁺ of Zn (CN) ₂ (R ² = CN), thereby In the presence of a suitable catalyst as described later, the coupling can be carried out in a suitable solvent, optionally with a suitable base as described later.

  For intermediate (4), for example, Y = Br.

  Examples of such coupling reactions are described in “Metal-Catalyzed Cross-Coupling Reactions”, Armin de Meijere (Editor), Francois Diederich (Editor) September 2004, Wiley Interscience ISBN: 978-3-527-30518-6. Can be found. .

The above coupling reaction is optionally performed in the presence of a suitable catalyst such as Pd (OAc) ₂ and P (oTol) ₃ , optionally with a suitable base such as potassium carbonate, and optionally a suitable such as THF. It is carried out in a solvent.

Also, as shown in Scheme 1 above, the substituted 2-amino-7-halo-quinoxaline intermediate (4) is a compound of formula R ^2a -Z where R ^2a is as defined above, Z is a "suitable functional group" as defined above, cup as above on the carbon with R ^2a group of R ^2a -Z compound via its functional groups Y for the formula (4) Coupled to a ring reaction, replacing the above Y with the above R ^2a group, thus providing the intermediate (5)) to the intermediate (5) compound by the above coupling reaction Can be done. Intermediate (5) can then be converted to a compound of general formula (I) by one or more further transformations. These changes can be, for example, cleavage of a protecting group, reduction or oxidation of a functional group, halogenation, metallation, substitution or other reactions known to those skilled in the art, such as amide bond formation.

Compounds and intermediates produced by the methods of the present invention may require purification. Purification of organic compounds is well known to those skilled in the art, and there can be several ways to purify the same compound. In some cases, purification may not be necessary. In some cases, the compound can be purified by crystallization. In some cases, the impurities can be removed by stirring with a suitable solvent. In some cases, the compound is chromatographed, in particular by flash chromatography, eg pre-packed silica gel cartridges, eg from Separtis, eg Isolute® flash silica gel or Isolute® flash NH ₂ silica gel Can be used in combination with a suitable chromatographic apparatus such as Flashmaster II (Separtis) or Isolera system (Biotage) and purified using an eluent such as a hexane / EtOAc or DCM / methanol gradient. In some cases, the compounds are combined by preparative HPLC, for example, combining a waters autopurifier equipped with a diode array detector and / or an on-line electrospray ionization mass spectrometer with a suitable pre-packed reverse phase column and water. And an eluent such as a gradient of acetonitrile (which may include additives such as trifluoroacetic acid or aqueous ammonia).

Analytical UPLC-MS was performed as follows.
Method A: Equipment: UPLC Acquity (Waters) equipped with PDA detector and Waters ZQ mass spectrometer; Column: Acquity BEH C18 1.7μm 2.1x50mm; Temperature: 60 ° C; Solvent A: Water + 0.1% Formic Acid; Solvent B: Acetonitrile; Gradient: 99% A → 1% A (1.6 min) → 1% A (0.4 min); Flow rate: 0.8 mL / min; Injection volume: 1.0 μl (0.1 mg-1 mg / mL sample concentration); Detection: PDA scan range 210-400 nm-fixed and ESI (+), scan range 170-800 m / z

  The names of the compounds were given using the Autonom 2000 add-in of ISIS / Draw [MDL Information Systems Inc. (Elsevier MDL)] or the ICS naming tool of ACD labs.

  Intermediate Example 1-1: Preparation of 1-bromo-4-chloro-imidazo [1,2-a] quinoxaline

  Step A: Preparation of 4-chloro-imidazo [1,2-a] quinoxaline

To a stirred suspension of 2-amino-3-chloroquinoxaline (25.5 g, 141.8 mmol) in water / THF 1: 1 (500 mL) was added 2-bromo-1,1-dioxy at room temperature. Ethoxyethane (83.8 g, 425.4 mmol) was added in one portion. After stirring for 1 hour at room temperature, the mixture was heated to reflux with stirring for 3 hours and then stirred for an additional 15 hours at room temperature. The pH of the mixture was adjusted to pH 8 by adding solid sodium carbonate, then the mixture was extracted with ethyl acetate (3 x 500 mL), and the combined organic extracts were dried over sodium sulfate. Removal of solvent gave 4-chloro-imidazo [1,2-a] quinoxaline as an orange-white solid (63 g, 93%): ¹ H-NMR (300 MHz, d ₆ -DMSO): δ = 9.05 (d, 1H), 8.51 (dd, 1H), 8.1 (dd, 1H), 7.99 (d, 1H), 7.89 (td, 1H), 7.76 (td, 1H) ppm. UPLC-MS: RT = 0.88 min; m / z 204.6 [MH ⁺ ]; Required MW = 203.6.

  Step B: Preparation of 1-bromo-4-chloro-imidazo [1,2-a] quinoxaline

To a stirred suspension of 4-chloro-imidazo [1,2-a] quinoxaline (28.9 g, 141.8 mmol) in THF / NMP 2: 1 (300 mL), NBS (25.2 g, 141.8 mmol) Was added in one portion at room temperature. After 18 hours of stirring, an additional 12.6 g (70.9 mmol) of NBS was added and the mixture was stirred for another 2 hours at room temperature. After removing the THF portion of the organic phase by vacuum evaporation, water was added (500 mL). The precipitate was filtered and the residue was washed with water and dried to provide 1-bromo-4-chloro-imidazo [1,2-a] quinoxaline as an off-white solid (35 g, 78.6 %): ¹ H-NMR (300 MHz, d ₆ -DMSO): δ = 14.22 (1H, s), 8.19 (1H, s), 7.75 (1H, d), 7.44 (2H, m) ppm. UPLC-MS: RT = 1.14 min; m / z 284.6 [MH ⁺ ]; MW required = 283.5.

  Intermediate Example 1-2: Preparation of 1-bromo-4-chloro-7,8-dimethylimidazo [1,2-a] quinoxaline

  Step A: Preparation of 6,7-dimethyl-1,4-dihydro-quinoxaline-2,3-dione

A mixture of 4,5-dimethylbenzene-1,2-diamine (60 g) and diethyl oxalate (600 mL) was heated under reflux for 1 hour and then cooled. The precipitate of 6,7-dimethyl-1,4-dihydro-quinoxaline-2,3-dione was filtered and washed with 96% ethanol to provide 38 g of the title compound. ESI-MS: m / z 191.1 [MH ⁺ ], 403.3 [2MNa ⁺ ]; Required MW = 190.2.

  Step B: Production of 2,3-dichloro-6,7-dimethylquinoxaline

6,7-dimethyl-1,4-dihydro-quinoxaline-2,3-dione (105 g), freshly distilled phosphoryl chloride (315 mL) and N, N-dimethylaniline (70 mL) were refluxed. Heated for minutes, then cooled and slowly poured into stirred ice water. The precipitate was filtered, washed with water and dried over KOH / P ₂ O ₅ ) in a vacuum desiccator. Extraction with benzene (3000 mL) and concentration of the filtered extract under reduced pressure gave 63 g of the title compound. ¹ H-NMR (300 MHz, d ₆ -DMSO): δ = 7.79 (2H, s), 2.45 (6H, s) ppm.

  Step C: Preparation of 3-chloro-6,7-dimethylquinoxalin-2-ylamine

A mixture of 2,3-dichloro-6,7-dimethylquinoxaline (30 g) in 300 mL THF was cooled with dry ice in a sealed vessel. Ammonia gas was added for 10 minutes, after which the mixture was heated to 100 ° C. for 20 hours. After removal of the solvent in vacuo, the residue was purified by flash chromatography to provide 14 g of the title compound. ¹ H-NMR (300 MHz, d ₆ -DMSO): δ = 7.43 (1H, s), 7.37 (1H, s), 7.00 (2H, s), 2.28 (6H, s) ppm.

  Step D: Preparation of 4-chloro-7,8-dimethylimidazo [1,2-a] quinoxaline

To a stirred suspension of 3-chloro-6,7-dimethylquinoxalin-2-ylamine (30.9 g, 0.16 mol) in water / THF 1: 1 (540 mL) at room temperature, bromoacetaldehyde diethyl acetal ( 94.6 g, 0.48 mol) and 5 g PPTS were added in one portion. After stirring for 1 hour at room temperature, the mixture was heated to reflux with stirring for 3 hours and then stirred for an additional 15 hours at room temperature. The pH value of the mixture was adjusted to pH 8 by addition of solid sodium carbonate. The precipitate that formed was filtered to provide 25 g of the title compound. ¹ H-NMR (300 MHz, d ₆ -DMSO): δ = 8.85 (1H, s), 8.19 (1H, s), 7.73 (1H, bs), 7.80 (1H, bs), 3.60 (6H, s) ppm.

  Step E: Preparation of 1-bromo-4-chloro-7,8-dimethylimidazo [1,2-a] quinoxaline

To a stirred suspension of 4-chloro-7,8-dimethylimidazo [1,2-a] quinoxaline (32.2 g, 0.148 mol) in THF / NMP 2: 1 (312 mL) was added NBS (26.3 g, 0.148 mol) was added once at room temperature. After 18 hours of stirring, more NBS (13.1 g, 0.074 mol) was added and the mixture was stirred at room temperature for an additional 2 hours. After removal of the THF portion of the organic phase by vacuum evaporation, water was added (520 mL). The precipitate was filtered and the residue was washed with water, diethyl ether and dried to provide 35 g of the title compound. ¹ H-NMR (300 MHz, d ₆ -DMSO): δ = 8.54 (1H, s), 7.75 (1H, s), 7.40 (1H, s), 2.20 (6H, s) ppm.

  Intermediate Example 1-3: Preparation of 1-bromo-4-chloro-7,8-difluoroimidazo [1,2-a] quinoxaline

  Step A: Preparation of 6,7-difluoro 1,4-dihydro-quinoxaline-2,3-dione

  6,7-Difluoro-1,4-dihydro-quinoxaline-2,3-dione was prepared similarly to the procedure for Intermediate Example 1-2, Step A to give the title compound in 90% yield.

  Step B: Preparation of 2,3-dichloro-6,7-difluoroquinoxaline

  2,3-Dichloro-6,7-difluoroquinoxaline was prepared similarly to the procedure for Intermediate Example 1-2, Step B to give the title compound in 60% yield.

  Step C: Preparation of 3-chloro-6,7-difluoroquinoxalin-2-ylamine

3-Chloro-6,7-difluoroquinoxalin-2-ylamine was prepared similarly to the procedure for Intermediate Example 1-2, Step C by stirring in DMF at room temperature for 20 hours and was titled 50% yield. To give a compound. ¹ H-NMR (300 MHz, d ₆ -DMSO): δ = 7.78 (1H, t), 7.51 (1H, t), 7.40 (2H, s) ppm.

  Step D: Preparation of 4-chloro-7,8-difluoroimidazo [1,2-a] quinoxaline

  4-Chloro-7,8-difluoroimidazo [1,2-a] quinoxaline was prepared similarly to the procedure for Intermediate Example 1-2, Step D to give the title compound in 75% yield.

  Step E: Preparation of 1-bromo-4-chloro-7,8-difluoroimidazo [1,2-a] quinoxaline

1-Bromo-4-chloro-7,8-difluoroimidazo [1,2-a] quinoxaline was prepared analogously to the procedure for Intermediate Example 1-2, Step E to give the title compound in 82% yield. It was. ¹ H-NMR (300 MHz, d ₆ -DMSO): δ = 9.00 (1H, t), 8.20 (1H, t), 7.92 (1H, s) ppm.

  Intermediate Example 1-4: Preparation of 1-bromo-4-chloro-8-fluoro-imidazo [1,2-a] quinoxaline

  Step A: Preparation of 6-fluoro-1,4-dihydro-quinoxaline-2,3-dione

  6-Fluoro-1,4-dihydro-quinoxaline-2,3-dione was prepared similarly to the procedure for Intermediate Example 1-2, Step A to give the title compound in 90% yield.

  Step B: Preparation of 2,3-dichloro-6-fluoro-quinoxaline

  2,3-Dichloro-6-fluoro-quinoxaline was prepared similarly to the procedure for Intermediate Example 1-2, Step B, to give the title compound in 60% yield.

  Step C: Preparation of 3-chloro-6-fluoro-quinoxalin-2-ylamine

  3-Chloro-6-fluoro-quinoxalin-2-ylamine was prepared similarly to the procedure for Intermediate Example 1-2, Step C by stirring in DMF at room temperature for 20 hours, yielding the title in 50% yield. A compound was obtained.

  Step D: Preparation of 4-chloro-8-fluoro-imidazo [1,2-a] quinoxaline

4-Chloro-8-fluoro-imidazo [1,2-a] quinoxaline was prepared similarly to the procedure for Intermediate Example 1-2, Step D, to give the title compound in 75%. ¹ H-NMR (300 MHz, d ₆ -DMSO): δ = 8.88 (1H, s), 8.40 (1H, d), 8.05 (1H, dd), 7.87 (1H, s), 7.52 (1H, t) ppm.

  Step E: Preparation of 1-bromo-4-chloro-8-fluoro-imidazo [1,2-a] quinoxaline

1-Bromo-4-chloro-8-fluoro-imidazo [1,2-a] quinoxaline was prepared similarly to the procedure for Intermediate Example 1-2, Step E, to give the title compound in 82% yield. . ¹ H-NMR (300 MHz, d ₆ -DMSO): δ = 8.79 (1H, d), 8.08 (1H, dt), 7.92 (1H, s), 7.59 (1H, t) ppm.

  Intermediate Example 1-5: Preparation of 1-bromo-4-chloro-7-cyano-imidazo [1,2-a] quinoxaline

  Step A: Preparation of 6-cyano-1,4-dihydro-quinoxaline-2,3-dione

6-Cyano-1,4-dihydro-quinoxaline-2,3-dione was prepared similarly to the procedure for Intermediate Example 1-2, Step A to give the title compound in 90% yield. ¹ H-NMR (300 MHz, d ₆ -DMSO): δ = 12.24 (1H, s), 12.13 (1H, s), 7.55 (1H, d), 7.40 (1H, s), 7.25 (1H, d) ppm.

  Step B: Preparation of 2,3-dichloro-6-cyano-quinoxaline

2,3-Dichloro-6-cyano-quinoxaline was prepared similarly to the procedure for Intermediate Example 1-2, Step B, to give the title compound in 50% yield. ¹ H-NMR (300 MHz, d ₆ -DMSO): δ = 8.79 (1H, s), 8.22 (2H, s) ppm.

  Step C: Preparation of 3-chloro-7-cyano-quinoxalin-2-ylamine

3-Chloro-7-cyano-quinoxalin-2-ylamine was prepared analogously to the procedure for Intermediate Example 1-2, Step C by stirring in DMF for 20 hours at room temperature, the title compound in 50% yield Got. ¹ H-NMR (300 MHz, d ₆ -DMSO): δ = 9.06 (1H, s), 8.62 (1H, d), 8.60 (1H, s), 8.24 (1H, d), 7.97 (1H, s) ppm.

  Step D: Preparation of 4-chloro-7-cyano-imidazo [1,2-a] quinoxaline

4-Chloro-7-cyano-imidazo [1,2-a] quinoxaline was prepared similarly to the procedure for Intermediate Example 1-2, Step D, to give the title compound in 75% yield. ESI-MS: m / z 229.1 [MH ⁺ ]; Required MW = 228.6

  Step E: Preparation of 1-bromo-4-chloro-7-cyano-imidazo [1,2-a] quinoxaline

1-Bromo-4-chloro-7-cyano-imidazo [1,2-a] quinoxaline was prepared similarly to the procedure for Intermediate Example 1-2, Step E, to give the title compound in 82% yield. . ¹ H-NMR (300 MHz, d ₆ -DMSO): δ = 9.31 (1H, d), 8.68 (1H, s), 8.23 (1H, d), 8.08 (1H, s) ppm.

  Intermediate Example 2-1: Preparation of (1-Bromo-imidazo [1,2-a] quinoxalin-4-yl) -isobutyl-amine

To a stirred solution of 1-bromo-4-chloro-imidazo [1,2-a] quinoxaline (14.13 g, 50 mmol) in NMP (400 mL) was added isobutylamine (9.94 mL, 100 mmol) and DIPEA. (26.13 mL, 150 mmol) was added in a microwave reactor at room temperature. The solution was heated at 170 ° C. for 60 minutes under microwave irradiation. After cooling, water is added to the solution, the precipitate is filtered, and the residue is washed with water, dried and (1-bromo-imidazo [1,2-a] quinoxalin-4-yl) -isobutyl -Provided amine (14.89 g, 93.3%): ¹ H-NMR (300 MHz, d ₆ -DMSO): δ = 9.17 (1H, d), 8.01 (1H, d), 7.92 (1H, s), 7.78 (1H, dd), 7.70 (1H, dd) ppm. UPLC-MS: RT = 1.14 min; m / z 284.6 [MH ⁺ ]; required MW = 283.5.

  Example 1-1: 1- [4- (4-Isobutylamino-imidazo [1,2-a] quinoxalin-1-yl) -phenyl] -3- [4- (4-methyl-piperazin-1-ylmethyl) -3-Trifluoromethyl-phenyl] -urea

1- [4- (4-Methyl-piperazin-1-ylmethyl) -3-trifluoromethyl-phenyl] -3- [4- (4,4,5,5-tetramethyl- [1,3,2] Dioxaborolan-2-yl) -phenyl] -urea (244 mg, 0.47 mmol) was added to potassium carbonate (1.41 mL, 1 M in water) and THF (1 mL) and stirred overnight at room temperature in a sealed vial. did. (1-Bromo-imidazo [1,2-a] quinoxalin-4-yl) -isobutyl-amine (75 mg, 0.235 mmol), Pd (OAc) ₂ (10.6 mg, 0.047 mmol) and P (oTol) ₃ ( 28.6 mg, 0.094 mmol) was added and the mixture was heated at 140 ° C. for 40 minutes under microwave irradiation. After cooling, the solution was filtered and subjected to preparative HPLC to give 1- [4- (4-isobutylamino-imidazo [1,2-a] quinoxalin-1-yl) -phenyl] -3- [4- ( 4-Methyl-piperazin-1-ylmethyl) -3-trifluoromethyl-phenyl] -urea was provided (24.8 mg, 14%): ¹ H-NMR (300 MHz, d ₆ -DMSO): δ = 9.30 ( 1H, s), 9.24 (1H, s), 7.98 (1H, s), 7.68-7.50 (6H, m), 7.47 (3H, m), 7.27 (2H, m), 6.93 (1H, dd), 3.51 (2H, s), 3.37 (2H, dd), 2.38 (8H, br s), 2.19 (3H, s), 2.09 (1H, sept), 0.91 (6H, d) ppm; UPLC-MS: RT = 1.03 Min; m / z (ES +) 631.7 [MH ⁺ ]; Required MW = 630.7.

  Example 1-2: Preparation of N-cyclopropyl-4- (4-isobutylamino-imidazo [1,2-a] quinoxalin-1-yl) -benzamide

(1-Bromo-imidazo [1,2-a] quinoxalin-4-yl) -isobutyl-amine (20 mg, 0.07 mmol), [4-[(cyclopropylamino) carbonyl] phenyl] -boronic acid (21.8 mg , 0.11 mmol), Pd (dppf) Cl ₂ (1.26 mg, 0.007 mmol) and potassium carbonate (212 μL, 1 M in water) are mixed in a sealed vial in 2 mL NMP and subjected to 140 under microwave irradiation. Heated at ° C for 40 minutes. After cooling, the solution was filtered and subjected to preparative HPLC to provide N-cyclopropyl-4- (4-isobutylamino-imidazo [1,2-a] quinoxalin-1-yl) -benzamide (2.86 mg , 10%): ¹ H-NMR (300 MHz, d ₆ -DMSO): δ = 8.60 (1H, d), 7.97 (2H, d), 7.71 (1H, t), 7.69 (2H, d), 7.54 (1H, d), 7.52 (1H, s), 7.28 (1H, dd), 7.19 (1H, d), 6.91 (1H, dd), 3.39 (2H, dd), 2.86 (1H, m), 2.09 ( 1H, sept), 0.96 (6H, d), 0.70 (2H, d), 0.55 (2H, d) ppm; UPLC-MS: RT = 1.14 min; m / z (ES +) 400.4 [MH ⁺ ]; required MW = 399.5.

  Example 1-3: Preparation of 1-ethyl-3- [4- (4-isobutylamino-imidazo [1,2-a] quinoxalin-1-yl) -phenyl] -urea

1-ethyl-3- [4- (4-isobutylamino-imidazo [1,2-a] quinoxalin-1-yl) -phenyl] -urea (21 mg, 20.6%) was replaced with 1-ethyl-3- [ Prepared as in Example 1.2 using 4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -urea (137 mg, 0.47 mmol). And subjected to preparative HPLC: ¹ H-NMR (300 MHz, d ₆ -DMSO): δ = 8.75 (1H, s), 7.62 (1H, t), 7.53 (3H, m), 7.44 (3H, m), 7.28 (2H, m), 6.91 (1H, dd), 6.26 (1H, dd), 3.37 (2H, dd), 3.12 (2H, m), 2.09 (1H, sept), 1.03 (3H, t ), 0.90 (6H, d) ppm; UPLC-MS: RT = 1.07 min; m / z (ES +) 403.5 [MH ⁺ ]; Required MW = 402.5.

  Example 1-4: Preparation of 1- (2,3-dihydro-1,4-benzodioxin-6-yl) -N- (2-methylpropyl) imidazo [1,2-a] quinoxalin-4-amine

0.1 mmol of (1-bromo-imidazo [1,2-a] quinoxalin-4-yl) -isobutyl-amine (Intermediate Example 2.1, 1 mL, 0.1 M in NMP), 0.15 mmol of 2,3-dihydro-1 , 4-Benzodioxin-6-ylboronic acid (0.3 mL, 0.5 M in NMP, 1.5 eq), 0.02 mmol Pd (dppf) Cl ₂ (0.533 mL, 0.0375 M in NMP, 0.2 eq) and 0.3 mmol K ₂ CO ₃ (0.3 mL, 1M in water, 3 eq) was mixed in a sealed vial and heated at 130 ° C. for 60 minutes under microwave irradiation. After cooling, the solution was filtered and subjected to preparative HPLC, 8.1 mg (22%) of 1- (2,3-dihydro-1,4-benzodioxin-6-yl) -N- (2-methylpropyl) ) Imidazo [1,2-a] quinoxalin-4-amine was provided. UPLC-MS: RT = = 1.26 min; m / z (ES +) 375.4 [MH ⁺ ]; MW required = 374.4.

  The following compounds were similarly prepared using the appropriate boronic acid derivative [LC-MS data such as retention time (RT in minutes) or observed mass peaks unless otherwise indicated using LC-MS Method A] Collected. ]

  Example 2.1: Preparation of N-cyclopropyl-4- [4- (2-hydroxy-ethylamino) -imidazo [1,2-a] quinoxalin-1-yl] -benzamide

(1-bromo-4-chloro-imidazo [1,2-a] quinoxaline (Intermediate Example 1.1, 1 mL, 0.2 M in NMP), 2-amino-ethanol (2 eq, 0.8 mL, 0.5 M in NMP) and DIPEA (3 eq, 103 μL) was mixed in a sealed vial and heated under microwave irradiation for 60 minutes at 170 ° C. After cooling, [4-[(cyclopropylamino) carbonyl] phenyl] -boron Acid (1.5 eq, 0.3 mL, 1 M in NMP), Pd (dppf) Cl ₂ (0.1 eq, 533 μL, 0.0375 M in NMP) and potassium carbonate (600 μL, 1 M in water) are added and the mixture is Heated for 40 minutes under microwave irradiation at 140 ° C. After cooling, the solution was filtered and subjected to preparative HPLC to give N-cyclopropyl-4- [4- (2-hydroxy-ethylamino) -imidazo [ 1,2-a] quinoxalin-1-yl] -benzamide provided (10.19 mg, 13%): UPLC-MS: RT = = 0.82 min; m / z (ES +) 388.4 [MH ⁺ ]; required MW = 387.4.

  The following compounds were similarly prepared using the appropriate intermediate example 1.x, the appropriate amine and the appropriate boronic acid derivative [LC-MS data such as retention time (RT in minutes) or observed mass peaks are particularly indicated Collected using LC-MS method A unless otherwise noted. ]

  Example 3.1: Preparation of 4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N- (1H-pyrazol-3-yl) benzamide

0.1 mmol 4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzoic acid (1.0 mL, 0.1 M in NMP) (Example 1.5), 0.2 mmol 1H-pyrazol-3-amine (1 mL, 0.5 M in NMP, 2 eq), 0.2 mmol HATU (1 mL, 0.5 M in NMP, 2 eq) and 0.4 mmol NMM (0.133 mL, 3 M in NMP, 4 equivalents), shaken at room temperature for 24 hours, subjected to preparative HPLC, and 7.6 mg of 4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxaline-1- Il} -N- (1H-pyrazol-3-yl) benzamide provided (18%): UPLC-MS: RT = 1.04 min; m / z (ES +) 426.5 [MH ⁺ ]; Required MW = 425.5.

  The following example compounds were similarly prepared using the appropriate amine [LC-MS data such as retention time (RT in minutes) or observed mass peaks were collected using LC-MS Method A unless otherwise indicated. did. ]

  Furthermore, the compounds of formula (I) of the present invention can be converted to any of the salts described herein by any method known to those skilled in the art. Similarly, any salt of the compound of formula (I) of the present invention may be converted to the free compound by any method known to those skilled in the art.

Pharmaceutical compositions of the compounds of the invention The invention also relates to pharmaceutical compositions comprising one or more compounds of the invention. These compositions can be used to achieve the desired pharmacological effect by administration to a patient in need thereof. For the purposes of the present invention, a patient is a mammal, including a human in need of treatment for a particular condition or disease. Thus, the present invention includes a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of the present invention or a salt thereof. The pharmaceutically acceptable carrier is preferably relatively non-toxic and harmless to the patient at a concentration that results in an active activity of the active ingredient, so that any side effects attributed to the carrier are those of the active ingredient. A carrier that does not reduce the value of the beneficial effects. A pharmaceutically effective amount of the compound is preferably that amount which results in or affects the particular condition being treated. The compounds of the present invention may be combined with pharmaceutically acceptable carriers well known in the art using any effective conventional dosage unit form including immediate release, sustained release and delayed release formulations, for example Orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally.

  For oral administration, the compounds can be prepared in solid or liquid formulations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions and emulsions, and for the production of pharmaceutical compositions Can be prepared by methods known in the art. The solid unit dosage form can be a capsule, which is of the usual hard or soft shell gelatin type including, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, calcium phosphate and corn starch Can be.

  In another embodiment, the compound of the invention comprises a conventional tablet base such as lactose, sucrose and corn starch, a binder such as gum arabic, corn starch or gelatin, potato starch, alginic acid, corn starch and guar gum, gum tragacanth, gum arabic. Disintegrants to aid tablet disintegration and dissolution after administration, such as lubricants to improve tablet granulation flow and prevent tablet material from sticking to the surface of the tablet die and punch, such as Talc, stearic acid, magnesium stearate, calcium stearate or zinc stearate, dyes, colorants, flavoring agents such as peppermint, wintergreen oil or cherry flavoring agents that enhance the aesthetic value of tablets and make them more acceptable to patients And can be tableted together. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents with or without the addition of pharmaceutically acceptable surfactants, suspending agents or emulsifiers, such as Water and alcohols such as ethanol, benzyl alcohol and polyethylene alcohol are mentioned. Various other materials may be present as a coating, or else may be present to alter the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both.

  Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in a mixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents as described above, may also be present.

  The pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion. The oily phase can be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifiers are (1) naturally derived gums such as gum arabic and tragacanth, (2) naturally derived phosphatides such as soy and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides such as Sorbitan monooleate, (4) A condensation product of the above partial ester and ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsion can also contain sweetening and flavoring agents.

  Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. The suspension may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate; one or more colorants; one or more flavoring agents; and one or more sweeteners, such as Sucrose or saccharin may also be included.

  Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain analgesics and preservatives, such as methyl and propyl parabens, and flavoring and coloring agents.

  The compounds of the invention may also be administered parenterally, ie subcutaneously, intravenously, intraocularly, intrasynovically, as an injectable dosage of the compound, preferably in a physiologically acceptable diluent with a pharmaceutical carrier. It can be administered intramuscularly or intraperitoneally. The pharmaceutical carrier can be a sterilized liquid or a liquid mixture thereof, such as water, saline, aqueous dextrose and related sugar solutions, alcohols such as ethanol, isopropanol or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol A ketal such as 2,2-dimethyl-1,1-dioxolane-4-methanol, ether such as poly (ethylene glycol) 400, oil, fatty acid, fatty acid ester or fatty acid glyceride, or acetylated fatty acid glyceride Pharmaceutically acceptable surfactants such as soaps or detergents, suspending agents such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose or carboxymethylcellulose, or emulsifiers Have fine other pharmaceutical auxiliary agent is added it may not be well or added.

  Specific examples of oils that can be used in the parenteral formulations of the present invention are those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil. is there. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include alkali metal, ammonium and triethanolamine salts of fatty acids; suitable detergents include cationic detergents such as dimethyldialkylammonium halides, alkylpyridinium halides, and alkylamine acetates; anions Detergents such as alkyl, aryl and olefin sulfonates, alkyl, olefins, ethers and monoglyceride sulfates and sulfosuccinates, nonionic detergents such as aliphatic amine oxides, fatty acid alkanolamides and poly (oxyethylene-oxy Propylene) or ethylene oxide or propylene oxide copolymers, and amphoteric detergents such as alkyl-β-aminopropionates and 2-alkylimidazolines quaternary ammonia Umushio, as well as mixtures thereof.

  The parenteral compositions of the invention will usually contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such a composition may comprise a non-ionic surfactant having a hydrophilic-hydrophobic balance (HLB) preferably from about 12 to about 17. it can. The amount of surfactant in such formulations is preferably in the range of about 5% to about 15% by weight. The surfactant may be a single component having the above HLB or may be a mixture of two or more components having the desired HLB.

  Examples of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, high molecular weight addition of sorbitan monooleate and hydrophobic bases formed by condensation of propylene glycol and propylene oxide with ethylene oxide It is a thing.

  The pharmaceutical compositions may be in the form of a sterile injectable aqueous suspension. Such suspensions may be formulated by known methods using the following: suitable dispersing or wetting agents and suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone , Tragacanth gum and gum arabic, dispersants or wetting agents (naturally occurring phosphatides such as lecithin, condensation products of fatty acids and alkylene oxides such as polyoxyethylene stearate, condensation products of long chain aliphatic alcohols and ethylene oxide, For example, condensation products of ethylene oxide with partial esters derived from heptadeca-ethyleneoxycetanol, fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or fatty acids And a condensation product of a partial ester and ethylene oxide derived from hexitol anhydride, such as polyoxyethylene sorbitan monooleate).

  The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that can be used are, for example, water, Ringer's solution, isotonic sodium chloride solution and isotonic glucose solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.

  The compositions of the present invention can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature, and therefore dissolves in the rectum to release the drug Will do. Such materials are, for example, cocoa butter and polyethylene glycol.

  Another formulation used in the methods of the present invention employs transdermal delivery devices (“patches”). Such transdermal patches can be used to perform continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The manufacture and use of transdermal patches for drug delivery is well known in the art (see US Pat. No. 5,023,252 issued Jun. 11, 1991, incorporated herein by reference). ). Such patches can be constructed to provide continuous, pulsatile or on-demand delivery of the drug.

  Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations known in the art.

  It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The manufacture and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. For example, direct techniques for administering drugs directly to the brain typically involve the placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system used for the delivery of drugs to specific anatomical regions of the body is described in US Pat. No. 5,011,472 issued April 30, 1991. .

  The compositions of the present invention may also include other conventional pharmaceutically acceptable formulation ingredients, commonly referred to as carriers or diluents, as necessary or desired. Conventional procedures for making such compositions in an appropriate dosage form can be used. Such ingredients and procedures include the following literature: Powell, MF et al. “Compendium of Excipients for Parenteral Formulations” PDA Journal of Pharmaceutical Science & Technology 1998, 52 (5), 238-311; Strickley, RG “Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999) -Part-1 "PDA Journal of Pharmaceutical Science & Technology 1999, 53 (6), 324-349; and Nema, S. et al." Excipients and Their Use in Injectable Products "PDA Journal of Pharmaceutical Science & Technology 1997, 51 (4), 166-171, each of which is incorporated herein by reference.

Commonly used pharmaceutical ingredients that can be used as appropriate to formulate the composition to suit the intended route of administration include the following:
Acidifying agents (for example, but not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid);
Alkaline agents (for example, but not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine) Not);
Adsorbents such as, but not limited to, powdered cellulose and activated carbon;
Aerosol propellants (eg, including but not limited to carbon dioxide, CCl ₂ F ₂ , F ₂ ClC—CClF ₂ and CClF ₃ );
Air displacement agents (for example, but not limited to, nitrogen and argon);
Antifungal preservatives (for example, but not limited to, benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate);
Antimicrobial preservatives (for example, but not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal);
Antioxidants (eg, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, Including, but not limited to, sodium metabisulfite);
Binding materials (for example, but not limited to, block polymers, natural and synthetic rubbers, polyacrylates, polyurethanes, silicones, polysiloxanes and styrene butadiene copolymers);

Buffering agents (including, but not limited to, potassium metaphosphate, dipotassium phosphate, sodium acetate, anhydrous sodium citrate and sodium citrate dihydrate);
Carrying agent (eg gum arabic syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection And bacteriostatic water for injection, but is not limited to this);
Chelating agents (including, but not limited to, edetate disodium and edetate);
Colorants (eg FD & C Red No. 3, FD & C Red No. 20, FD & C Yellow No. 6, FD & C Blue No. 2, D & C Green No. 5, D & C Orange No. 5, D & C Red No. 8, Caramel and Red Including but not limited to ferric oxide);
Fining agents (for example, but not limited to bentonite);
Emulsifiers (for example, but not limited to, gum arabic, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate);
Encapsulating agents (for example, but not limited to gelatin and cellulose acetate phthalate)
Perfume (for example, but not limited to, anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin);
Humectants (for example, but not limited to, glycerol, propylene glycol and sorbitol);
Emollients (for example, but not limited to, mineral oil and glycerin);
Oils (for example, but not limited to, peanut oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil);

Ointment bases (for example, but not limited to, lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment and rose perfume ointment);
Penetration enhancers (transdermal delivery) (eg monohydroxy or polyhydroxy alcohols, mono- or polyhydric alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty acid esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl) Derivatives, cephalins, terpenes, amides, ethers, ketones and ureas, including but not limited to)
Plasticizers such as, but not limited to, diethyl phthalate and glycerol;
Solvents such as ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection, and sterile water for washing, Not limited to);
Hardeners (for example, but not limited to, cetyl alcohol, cetyl ester wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax);
Suppository bases (for example, but not limited to, cocoa butter and polyethylene glycols (mixtures));
Surfactants such as, but not limited to, benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan monopalmitate;
Suspension agents (for example, but not limited to, agar, bentonite, carbomer, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, kaolin, methylcellulose, tragacanth and veegum);

Sweeteners such as, but not limited to, aspartame, dextrose, glycerol, mannitol, propylene glycol, sodium saccharin, sorbitol and sucrose;
Tablet anti-adhesives (for example, but not limited to, magnesium stearate and talc);
Tablet binders such as but not limited to gum arabic, alginic acid, sodium carboxymethylcellulose, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone and pregelatinized starch );
Tablet and capsule diluents (including but not limited to dicalcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch) ,);
Tablet coatings (for example, but not limited to, liquid glucose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac);
Tablet direct compression excipients such as, but not limited to, dicalcium phosphate;
Tablet disintegrants (for example, but not limited to, alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrilin potassium, crosslinked polyvinylpyrrolidone, sodium alginate, sodium starch glycolate and starch);

Tablet lubricants (including but not limited to colloidal silica, corn starch and talc);
Tablet lubricants (including but not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate);
Tablet / capsule opacifier (for example, but not limited to titanium dioxide);
Tablet abrasives such as, but not limited to, carnauba wax and white wax;
Thickeners (for example, but not limited to, beeswax, cetyl alcohol and paraffin);
Isotonic agents (for example, but not limited to, dextrose and sodium chloride);
Viscosity increasing agents (for example, but not limited to, alginic acid, bentonite, carbomer, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, sodium alginate and tragacanth), and
Wetting agents (for example, but not limited to, heptadecaethyleneoxycetanol, lecithin, sorbitol monooleate, polyoxyethylene sorbitol monooleate and polyoxyethylene stearate).

The pharmaceutical composition according to the present invention can be exemplified as follows.
Sterile IV solution: A 5 mg / mL solution of the desired compound of the invention can be prepared using sterile injectable water and the pH adjusted if necessary. This solution is diluted to 1-2 mg / mL for administration with sterile 5% dextrose and administered as an IV infusion over approximately 60 minutes.

  IV Lyophilized powder for administration: a sterile formulation comprising (i) 100-1000 mg of the desired compound of the invention as a lyophilized powder, (ii) 32-327 mg / mL sodium citrate, and (iii) can be prepared using 300-3000 mg of Dextran 40. This formulation is reconstituted to a concentration of 10-20 mg / mL with sterile injectable saline or 5% dextrose and further diluted to 0.2-0.4 mg / mL with 5% saline or dextrose. And by IV bolus or IV infusion over 15-60 minutes.

Intramuscular suspension: The following solutions or suspensions can be prepared for intramuscular injection:
50 mg / mL of the desired water-insoluble compound of the invention
5 mg / mL sodium carboxymethylcellulose
4 mg / mL TWEEN 80
9 mg / mL sodium chloride
9 mg / mL benzyl alcohol

  Hard shell capsules: Multi-unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg powdered active ingredient, 150 mg lactose, 50 mg cellulose and 6 mg magnesium stearate.

  Soft gelatin capsules: A mixture of active ingredients in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and poured into molten gelatin by a positive displacement pump to produce a soft gelatin capsule containing 100 mg of the active ingredient Form. The capsule is washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible pharmaceutical mix.

  Tablets: Numerous tablets so that the dosage unit is 100 mg active ingredient, 0.2 mg colloidal silicon dioxide, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch and 98.8 mg lactose. Prepare by conventional procedures. Appropriate aqueous and non-aqueous coatings can be applied, thereby improving taste, improving elegance and stability, or delaying absorption.

  Rapid release tablets / capsules: These are solid oral dosage forms made by conventional and novel methods. These dosage units are taken orally without water for rapid dissolution and delivery of the medicament. The active ingredient is mixed in a liquid containing ingredients such as sugar, gelatin, pectin and sweeteners. These liquids are lyophilized and solidified into solid tablets or caplets by solid phase extraction techniques. The pharmaceutical compound can be compressed with viscoelastic and thermoelastic saccharides and polymers or effervescent components, thereby producing a porous matrix intended for rapid release without the need for water.

Combination Therapy The compounds of the present invention can be administered as a single medicament or in combination with one or more other medicaments that do not produce unacceptable adverse effects. The present invention also relates to such a combination. For example, the compounds of the present invention can be combined with known anti-hyperproliferative or other indication drugs, and can also be combined with mixtures and combinations thereof. Other indications include, but are not limited to, antiangiogenic agents, mitotic inhibitors, alkylating agents, antimetabolites, DNA intercalating antibiotics, growth factor inhibitors, cell cycle inhibition Agents, enzyme inhibitors, toposisomerase inhibitors, biological response modifiers or antihormones.

  Additional medications include aldesleukin, alendronate, alfaferone, alitrenoin, allopurinol, aloprim, aloxi, altretamine, aminoglutethimide, amifostine, amrubicin , Amsacrine, anastrozole, anzmet, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine, azathioprine, BCG or Thais BCG, bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sul Fate, broxuridine, bortezomib, busulfan, calcitonin, campus, capecitabine, carboplatin, casodex, cefesone, sermoloy Celmoleukin, cerubidine, chlorambucil, cisplatin, cladribine, cladribine, clodronic acid, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunoxome (DaunoXome), decadron, decadron phosphate, delestrogen, Denileukin diftitox, depo-medrol, deslorelin, dexrazoxane, diethylstilbestrol, diflucan, docetaxel, droxyfluridine, doxorubicin, dronabinol, DW-166HC, elligard , Elitek, ellence, emend, epirubicin, epoetin alfa, epogen, eptaplatin, ergamisol, es Estrace, estradiol, estramustine sodium phosphate, ethinyl estradiol, etyol, etidolic acid, etopophos, etoposide, fadrozole, farston, filgrastim, finasteride, fligrastim, Floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, formestane, fosterabine, fotemustine, fulvestrant, gamma Guard (gammagard), gemcitabine, gemtuzumab, gleevec, gliadel, goserelin, granisetron HCl, histrelin, hycamtin, hydroco Hydrocortone, eyrthro-hydroxynonyladenine, hydroxyurea, ibritumomab tiusetan, idarubicin, ifosfamide, interferon α, interferon-α2, interferon α-2A, interferon α-2B, interferon α-n1 , Interferon α-n3, interferon β, interferon γ-1a, interleukin-2, intron A, iressa, irinotecan, kaitril, lentinan sulfate, letrozole, leucovorin, leuprolide, leuprolide acetate, levamisole, levofolinic acid Calcium salt, levothroid, levoxyl, lomustine, lonidamine, marinol, mechlorethamine, mecobalamin, acetate Roxiprogesterone, megestrol acetate, melphalan, menest, 6-mercaptopurine, mesna, methotrexate, metvix, miltefosine, minocycline, mitomycin C, mitoxantrone, mitoxantrone, modrenal , Myocet, Nedaplatin, Neulasta, Neumega, Neupogen, Nilutamide, Norbadex, NSC-631570, OCT-43, Octreotide, Ondansetron HCl, Orapred, Oxaliplatin, Paclitaxel, pediapred (pediapred), pegaspargase, pegasis, pentostatin, picibanil, pilocarpine HCl, pirarubicin, prikamycin, porfimer sodium, prednime Prednimustine, prednisolone, prednisone, premarin, procarbazine, procrit, raltitrexed, raltitrexed, rebif, rhenium-186 etidronate, rituximab, roferon-A, romurtide, salam salagen), sandstatin, salgramostim, semstine, sizofiran, sobuzoxane, soleumedol, sparfosic acid, stem cell therapy, streptozocin, strontium-89 chloride, synthroid, tamoxifen, Tamsulosin, tasonermin, tastolactone, taxotere, teceleukin, temozolomide, teniposide, testosterone propionate, testred , Thioguanine, thiotepa, thyroid stimulating hormone, tiludronate, topotecan, toremifene, tositumomab, trastuzumab, treosulfan, tretinoin, trexall, trimethylmelamine, trimethrexate, triptorelin acetate , Triptorelin acetate (triptorelin acetate), RDEA119, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, virulizin, ginecard (zinecard), dinostatin stimamarer, zofuran, ABI-007 (Acolbifene), actimune, affinitak, aminopterin, arzoxifene, asoprisnil, atamestane Atrasentan, sorafenib, avastin, CCI-779, CDC-501, celebrex, cetuximab, crisnatol, cyproterone acetate, decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, edtecaline (Edotecarin), eflornithine, exatecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implant, holmium-166 DOTMP, ibandronic acid, interferon gamma, intron PEG, ixabepilone, keyhole limpet hemocyanin , L-651582, lanreotide, lasofoxifene, libra, lonafarnib, miproxifene, minodronate, MS-209, liposomal MTP-PE, MX -6, nafarelin, nemorubicin, neovastat, nolatrexed, oblimersen, onco-TCS, osidem, paclitaxel polyglutamate, disodium pamidronate, PN -401, QS-21, quazepam, R-1549, raloxifene, ranpirnase, 13-cis-retinoic acid, satraplatin, seocalcitol, T-138067, tarceva, taxoprexin, Thymosin α1, tiazofurine, tipifarnib, tirapazamine, TLK-286, toremifene, trans-MID-107R, valspodar, vapreotide, vatalanib, verteporfin, vinflunin, vinflunin -100, zoledronic acid and And combinations thereof.

  Optional anti-hyperproliferative agents that may be added to the composition include, but are not limited to, cancer chemotherapy in the 11th edition, the Merck Index, (1996) (incorporated herein by reference). The compounds listed in the pharmaceutical regime include, for example, asparaginase, bleomycin, carboplatin, karmastin, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycin (Adriamycine)), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotreki Over DOO, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene (raloxifen), streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine and vindesine.

  Other anti-hyperproliferative agents suitable for use in the compositions of the present invention include, but are not limited to, Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th edition), edited by Molinoff et al., McGraw-Hill, pages 1225-1287, (1996) (incorporated herein by reference) include compounds recognized in the treatment of neoplastic diseases, such as aminoglutethimide, L-asparaginase, azathioprine, 5- Azacitidine cladribine, busulfan, diethylstilbestrol, 2 ', 2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyl adenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine Phosphate, fluoxymesterone, flutamide, capron Hydroxyprogesterone, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotan, paclitaxel, pentostatin, N-phosphonoacetyl-L aspartate (PALA), pricamycin, semustine, teniposide, testosterone, propionate Thiotepa, trimethylmelamine, uridine and vinorelbine.

  Other anti-hyperproliferative agents suitable for use in the compositions of the present invention include, but are not limited to, other anticancer agents such as epothilone and its derivatives, irinotecan, raloxifen and topotecan. .

  The compounds of the present invention can also be administered in combination with protein therapy. Such protein therapeutic methods suitable for the treatment of cancer and other angiogenic diseases and suitable for use with the compositions of the present invention include, but are not limited to, interferons (eg, interferon α, β or γ), Super agonist monoclonal antibody, Tubingen, TRP-1 protein vaccine, Colostrinin, anti-FAP antibody, YH-16, gemtuzumab, infliximab, cetuximab, trastuzumab, denileukin, diftitox, rituximab, thymosin α1 , Bevacizumab, mecasermin, mecasermin rinfabate, oprelvekin, natalizumab, rhMBL, MFE-CP1 + ZD-2767-P, ABT-828, ErbB2-specific antitoxin, SGN -35, MT-103, rinfabate, AS-1402, B43 -Genistein, L-19-based radiation therapy, AC-9301, NY-ESO-1 vaccine, IMC-1C11, CT-322, rhCC10, r (m) CRP, MORAb-009, abiscumine, MDX- 1307, Her-2 vaccine, APC-8024, NGR-hTNF, rhH1.3, IGN-311, endostatin, borociximab, PRO-1762, lexatumumab, SGN-40, pertuzumab, EMD -273063, L19-IL-2 fusion protein, PRX-321, CNTO-328, MDX-214, tigapotide, CAT-3888, lavetuzumab, alpha particle-emitting radioisotope-bound lintuzumab , EM-1421, hyperacute vaccine, tucotuzumab (tucotuzumab), celmoleukin, galiximab, HPV-16-E7, javelin-prostate cancer, javelin-melanoma, NY-ESO-1 vaccine, EGF vaccine , CYT-004- MelQbG10, WT1 peptide, oregovomab (oregovom ab), ofatumumab, zalutumumab, cintredekin besudotox, WX-G250, Albuferon, aflibercept, denosumab, vaccine, CTP-37, Efungab (Efungumab) or 131I-chTNT-1 / B. Monoclonal antibodies useful as protein therapeutics include, but are not limited to, muromonab-CD3, abciximab, edrecolomab, daclizumab, gentuzumab, alemtuzumab, ibritumomab (ibritumomab), cetuximab, cetuximab bevicizumab), efalizumab, adalimumab, omalizumab, muromomab-CD3, rituximab, daclizumab, trastuzumab, palivizumab, basilixumab and infliximab.

In general, the use of cytotoxic drugs and / or mitotic inhibitors in combination with the compounds or compositions of the invention plays the following role:
(1) Compared with administration of any drug alone, the efficiency of suppressing tumor growth is improved or even the tumor is eliminated.
(2) The chemotherapeutic agent is administered at a smaller dose.
(3) Provide patients with well-tolerated chemotherapy with fewer adverse pharmacological complications than observed with single-agent chemotherapy and certain other combination therapies.
(4) To provide a treatment for a wide range of different cancer types in mammals, particularly humans.
(5) Provide higher response rate to treated patients.
(6) Provide longer survival time for treated patients compared to standard chemotherapy.
(7) Provide longer time for tumor to progress. And / or
(8) Compared to known examples where other anticancer drug combinations produce antagonism, results in efficacy and tolerability results that are at least as good as drugs used alone.

Methods for Sensitizing Cells to Radiation In one distinct embodiment of the invention, the compounds of the invention can be used to sensitize cells to radiation. That is, treatment of cells with a compound of the present invention prior to radiotherapy makes the cells more susceptible to DNA damage and cell death than when cells are not treated with a compound of the present invention. In one embodiment, the cells are treated with at least one compound of the invention.

  Thus, the present invention also provides a method of killing a cell, wherein one or more compounds of the present invention are administered to the cell in combination with conventional radiation therapy.

  The present invention also provides a method of making a cell susceptible to cell death by treating the cell with one or more compounds of the present invention prior to treatment of the cell to cause or induce cell death. In one embodiment, after treating a cell with one or more compounds of the invention, the cell is treated with at least one compound or at least one method or combination thereof, thereby inhibiting normal cell function. Or it causes DNA damage for the purpose of killing cells.

  In one embodiment, the cells are killed by treating the cells with at least one DNA damaging agent. That is, after treating a cell with one or more compounds of the invention, thereby sensitizing the cell to cell death, the cell is killed by treating the cell with at least one DNA damaging agent. DNA damaging agents useful in the present invention include, but are not limited to, chemotherapeutic agents (eg, cisplatin), ionizing radiation (X-rays, ultraviolet light), carcinogenic agents, and mutagenic agents.

  In another embodiment, cells are killed by treating the cells by at least one method to cause or induce DNA damage. Such methods include, but are not limited to, activation of cell signal pathways that cause DNA damage when cell signaling pathways are activated, and cell signals that cause DNA damage when cell signaling pathways are inhibited. Inhibition of the pathway and induction of biochemical changes within the cell where biochemical changes result in DNA damage. As a non-limiting example, the DNA repair pathway in the cell can be inhibited, thereby suppressing the repair of DNA damage and resulting in abnormal accumulation of DNA damage in the cell.

  In one embodiment of the invention, the compounds of the invention are administered to cells prior to induction of radiation or other intracellular DNA damage. In another embodiment of the invention, the compounds of the invention are administered to cells simultaneously with induction of DNA damage in radiation or other cells. In yet another embodiment of the invention, the compound of the invention is administered to a cell immediately after the initiation of induction of DNA damage in radiation or other cells.

  In another embodiment, the cell is in vitro. In another embodiment, the cell is in vivo.

  As noted above, the compounds of the present invention were surprisingly found to effectively inhibit Mps-1, and thus uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune response or inappropriate A disease of a cellular inflammatory response, or a disease associated with uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response, in particular uncontrolled cell growth, proliferation and Diseases in which survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is mediated by Mps-1, such as hematological tumors, solid tumors and / or metastases thereof, such as leukemia and myelodysplastic syndrome, Malignant lymphoma, head and neck tumors including brain tumors and brain metastases, non-small and small cell lung tumors, gastrointestinal tumors, endocrine tumors, breast tumors including mammary gland and other gynecological tumors, renal tumors, bladder tumors Urological tumors, including fine prostate tumors may be used for the treatment or prevention of skin tumors and sarcomas and / or metastases thereof.

  Therefore, according to another aspect, the present invention provides a compound of general formula (I) as described and defined herein for use in the treatment or prevention of a disease as described above, or , Its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, in particular pharmaceutically acceptable salts, or mixtures thereof.

  Therefore, another specific embodiment of the present invention is a compound of the above general formula (I), or a stereoisomer, tautomer, N-oxide, hydration thereof for the treatment or prevention of diseases. Products, solvates or salts, in particular pharmaceutically acceptable salts, or mixtures thereof.

  Therefore, another particular aspect of the present invention is the use of a compound of general formula (I) as described above for the manufacture of a pharmaceutical composition for the treatment or prevention of diseases.

  Diseases referenced in the previous two paragraphs are diseases of uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune response or inappropriate cell inflammatory response, or uncontrolled cell growth, proliferation and / or Or diseases associated with survival, inappropriate cellular immune response or inappropriate cellular inflammatory response, especially uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune response or inappropriate cellular inflammation Diseases whose response is mediated by Mps-1, such as hematological tumors, solid tumors and / or metastases thereof, such as head and neck tumors including leukemia and myelodysplastic syndrome, malignant lymphoma, brain tumors and brain metastases, non-small cells And breast tumors including small cell lung tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors including kidney tumors, bladder tumors and prostate tumors, skin tumors and It is a tumor and / or metastases thereof.

  The term “inappropriate” as used herein is preferably in the context of the present invention, in particular in the context of an “inappropriate cellular immune response” or “inappropriate cellular inflammatory response”. It should be understood to mean an under- or over-normal response that is related to and causes or causes the pathology of the disease.

  Preferably, the use is in the treatment or prevention of diseases that are hematological tumors, solid tumors and / or metastases thereof.

The present invention relates to methods of using the compounds of the present invention and compositions thereof for the treatment of hyperproliferative diseases in mammals. The compounds can be used to inhibit, inhibit, reduce, reduce, etc. cell proliferation and / or cell division and / or cause apoptosis. The method comprises an effective amount of a compound of the invention for treating a disease, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof, etc. Administering to a mammal, including a human in need thereof. Hyperproliferative disorders include but are not limited to, for example, psoriasis, keloids and other hyperplasias that affect the skin, benign prostatic hyperplasia (BPH), solid tumors such as breast cancer, respiratory tract cancer, brain cancer, genitals Examples include cancer, gastrointestinal cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and their distant metastasis. Diseases also include lymphomas, sarcomas and leukemias.

  Examples of breast cancer include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, non-invasive ductal carcinoma, and non-invasive lobular carcinoma.

  Examples of airway cancers include, but are not limited to, small cell lung cancer and non-small cell lung cancer, and bronchial adenoma and pleuropulmonary blastoma.

  Examples of brain cancer include, but are not limited to, brainstem glioma and hypothalamic glioma, cerebellar astrocytoma and cerebral astrocytoma, medulloblastoma, ependymoma, and neuroectodermal and pineal tumors Can be mentioned.

  Male genital tumors include, but are not limited to, prostate cancer and testicular cancer. Tumors of female genital organs include, but are not limited to, endometrial cancer, uterine cancer, ovarian cancer, vaginal cancer and vulvar cancer, and uterine sarcoma.

  Gastrointestinal tumors include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, pancreatic cancer, rectal cancer, small intestine cancer and salivary gland cancer.

  Tumors of the urinary tract include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureteral cancer, urethral cancer, and human papillary renal cancer.

  Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.

  Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (hepatocellular carcinoma with or without fibrotic lamellar variants), cholangiocellular carcinoma (intrahepatic cholangiocarcinoma) and mixed hepatobiliary cell carcinoma. It is done.

  Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

  Head and neck cancers include, but are not limited to, laryngeal cancer, hypopharynx, nasopharynx, oropharyngeal cancer, lip and laryngeal and oral cavity cancer, and squamous cell carcinoma. Lymphomas include, but are not limited to, AIDS-related lymphomas, non-Hodgkin lymphomas, cutaneous T-cell lymphomas, Burkitt lymphomas, Hodgkin's disease, and central nervous system lymphomas.

  Sarcomas include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

  Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia and hairy cell leukemia.

  Although these diseases are well characterized in humans, they exist with similar etiology in other mammals and can be treated by administering the pharmaceutical composition of the present invention.

  The term “treat” or “treatment”, as used throughout this specification, is conventionally used, for example, to combat, alleviate, reduce, release, ameliorate disease or disease symptoms such as cancer. It is management or care of the subject for the purpose of doing.

The present invention also provides a method for treating a disease associated with abnormal mitogen extracellular kinase activity, including, but not limited to, stroke, heart failure, hepatomegaly, cardiac hypertrophy Diabetes, Alzheimer's disease, cystic fibrosis, xenograft rejection symptoms, septic shock or asthma.

  Effective amounts of the compounds of the present invention can be used to treat such diseases, including the diseases (eg, cancer) described in the background section above. Nevertheless, such cancers and other diseases can be treated with the compounds of the present invention regardless of the mechanism of action and / or the relationship between the kinase and the disease.

  The term “abnormal kinase activity” or “abnormal tyrosine kinase activity” includes abnormal expression or activity of a gene or polypeptide encoding the kinase. Examples of such abnormal activity include, but are not limited to, gene or polypeptide overexpression; gene amplification; mutations that result in constitutively active or hyperactive kinase activity; gene mutations, deletions, substitutions, Addition etc. are mentioned.

  The present invention also provides a method for inhibiting the activity of kinase activity, particularly mitogenic extracellular kinase activity, which comprises an effective amount of a compound of the invention (its salt, polymorph, metabolite, hydration). Product, solvate, prodrug (eg, ester) and diastereoisomeric forms thereof. Kinase activity can be inhibited intracellularly (eg, in vitro) or can be inhibited in cells of a mammalian subject in need of treatment, particularly a human patient.

Methods of treating angiogenic diseases The present invention also provides methods of treating diseases and disorders associated with excess and / or abnormal angiogenesis.

  Inappropriate and ectopic expression of angiogenesis can be harmful to the organism. Many pathologies are associated with exogenous blood vessel growth. These pathologies include, for example, diabetic retinopathy, ischemic retinal vein occlusion and retinopathy of prematurity (Aiello et al. New Engl. J. Med. 1994, 331, 1480; Peer et al. Lab. Invest. 1995, 72, 638). ), Age-related macular degeneration (see AMD; Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855), neovascular glaucoma, psoriasis, posterior lens fibroproliferation, angiofibroma, inflammation, joints Examples include rheumatism (RA), restenosis, in-stent restenosis, and vascular stenosis. Furthermore, the increased vascular supply associated with cancer and neoplastic tissue promotes growth, leading to rapid tumor growth and metastasis. In addition, proliferation of neovascular and lymphatic vessels in tumors provides an escape route for revolt cells, promotes metastasis, and leads to cancer spread. Thus, the compounds of the present invention inhibit, block, alleviate, reduce, etc., for example, by inhibiting and / or reducing angiogenesis; It can be used to treat and / or prevent any of the above-mentioned angiogenic diseases by causing cell death or apoptosis of such cell types.

Dosage and Administration Treatment of the above symptoms in mammals by standard toxicity tests based on standard experimental techniques known to evaluate compounds useful in the treatment of hyperproliferative and angiogenic diseases Effective administration of the compounds of the invention by standard pharmacological assays for the determination of and by comparing these results with the results of known pharmaceutical agents used to treat these symptoms The amount can be readily determined for the treatment of each desired indication. The amount of active ingredient administered in the treatment of one of these conditions depends on the particular compound and dosage unit used, the mode of administration, the duration of treatment, the age and sex of the patient being treated, the condition being treated It can vary widely depending on considerations such as the nature and extent of the.

  The total amount of active ingredient administered is generally in the range of about 0.001 mg / kg to about 200 mg / kg body weight / day, and preferably about 0.01 mg / kg to about 20 mg / kg body weight / day. . A clinically useful dosing schedule would be 1 to 3 doses per day to 1 dose every 4 weeks. Furthermore, a “drug holiday” in which a patient is not dosed for a certain period of time may be advantageous for the overall balance between pharmacological effects and tolerance. A unit drug may contain from about 0.5 mg to about 1500 mg of the active ingredient and can be administered one or more times per day or less than once per day. The average daily dosage by infusion, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg / kg total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg / kg total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg / kg total body weight. The average daily dosage regimen will preferably be 0.1 to 200 mg administered and will be administered 1 to 4 times daily. The transdermal concentration will preferably be that required to maintain a daily dosage of 0.01 to 200 mg / kg. The average daily inhalation regimen will preferably be from 0.01 to 100 mg / kg total body weight.

  Of course, the specific initial and continued dosing regimen for each patient will depend on the nature and severity of the symptoms as determined by the diagnosing physician in charge, the activity of the particular compound used, the patient's age and general symptoms, administration It will vary with time, route of administration, drug excretion rate, drug combination, and the like. The desired mode of treatment and the frequency of administration of the compound of the invention, its pharmaceutically acceptable salt or ester, or its composition can be ascertained by one skilled in the art using conventional therapeutic tests.

  Preferably, the disease of the above method is a hematological tumor, a solid tumor and / or a metastasis thereof.

  The compounds of the present invention can be used in the treatment and prevention of tumor growth and metastasis, particularly solid tumors of all signs and stages with or without prior treatment of tumor growth, in particular prevention.

Methods for testing specific pharmacological or pharmaceutical properties are well known to those skilled in the art.
The example test experiments described herein serve to illustrate the invention and the invention is not limited to the examples shown.

Biological Assay: Proliferation Assay Cultured HeLa human cervical tumor cells (ATCC CCL-2) are 96-well multititer in 200 μl DMEM / HAMS F12 medium supplemented with 2 mM L-glutamine and 10% fetal calf serum Plated at a density of 3000 cells / well in the plate. After 24 hours, cells on one plate (zero plate) are stained with crystal violet (see below), while the medium on the other plate is replaced with fresh medium (200 μl) and test substances are added at various concentrations (0 μM, range of 0.01-30 μM, final concentration of solvent dimethyl sulfoxide was 0.5%). Cells were incubated for 4 days in the presence of test substances. Cell proliferation was determined by staining the cells with crystal violet. Cells were fixed by adding 11% glutaraldehyde solution at 20 μl / measuring point for 15 minutes at room temperature. After the fixed cells were washed three times with water, the plates were dried at room temperature. Cells were stained by adding 0.1% crystal violet solution (pH 3.0) at 100 μL / measurement point. After the stained cells were washed three times with water, the plates were dried at room temperature. The dye was dissolved by adding 10% acetic acid solution at 100 μl / measurement point. Absorbance was measured by photometry at a wavelength of 595 nm. The change in the number of cells in percent was calculated by normalizing the measurement to the absorbance value of the zero point plate (= 0%) and the absorbance value of the untreated (0 μM) cells (= 100%). IC50 values were determined using a 4-parameter approximation using in-house software.

Mps-1 kinase assay The human kinase Mps-1 phosphorylates a biotinylated substrate peptide. Phosphorylated product was detected by homogeneous time-resolved fluorescence resonance energy transfer from europium-labeled anti-phosphorylated serine / threonine antibody as donor to streptavidin labeled with cross-linked allophycocyanin (SA-XLent) as acceptor ( HTRF). Compounds are tested for inhibition of kinase activity. Human full-length recombinant Mps-1 kinase (purchased from Invitrogen, Karslruhe, Germany, catalog number PV4071) containing a GST-tag at the N-terminus was used. A biotinylated peptide with the amino acid sequence PWDPDDADITEILG (C-terminus of the amide, purchased from Biosynthan GmbH, Berlin) was used as a substrate for the kinase reaction.

For the assay, 50 nl of a 100-fold concentrate of the test compound in DMSO was pipetted into a black low volume 384 well microtiter plate (Greiner Bio-One, Frickenhausen, Germany) and assay buffer of Mps-1 [0.1 2 μl of a solution in mM sodium orthovanadate, 10 mM MgCl ₂ , 2 mM DTT, 25 mM Hepes pH 7.7, 0.05% BSA, 0.001% Pluronic F-127] is added and the mixture is incubated at 22 ° C. for 15 minutes Thus, the test compound was pre-bound to Mps-1 before the start of the kinase reaction. The kinase reaction was then initiated by adding 3 μl of a solution of 16.7 μM ATP and 1.67 μM peptide in assay buffer and the resulting mixture was incubated at 22 ° C. for a reaction time of 60 minutes. The concentration of Mps-1 in the assay was adjusted to the activity of the enzyme lot and was selected appropriately so that the assay was in the linear range, with typical enzyme concentrations in the range of approximately 1 nM (5 μl assay). Final concentration in volume). 3 μl of HTRF detection reagent solution (100 mM Hepes pH 7.4, 0.1% BSA, 40 mM EDTA, 140 nM Streptavidin-XLent [# 61GSTXLB, Fa. Cis Biointernational, Marcoule, France], 1.5 nM anti-phosphorylation ( The reaction was stopped by adding serine / threonine) -europium antibody [# AD0180, PerkinElmer LAS, Rodgau-Jugesheim, Germany].

  The resulting mixture was incubated at 22 ° C. for 1 hour to allow the phosphorylated peptide to bind to the anti-phosphorylated (serine / threonine) -europium antibody. The amount of phosphorylated substrate was then evaluated by measuring the resonance energy transfer from a europium labeled anti-phosphorylated (serine / threonine) antibody to streptavidin-XLent. Therefore, the amount of fluorescence emission at 620 nm and 665 nm after excitation at 350 nm was measured with an HTRF reader such as Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (PerkinElmer LAS, Rodgau-Jugesheim, Germany). The ratio of the amount of luminescence at 665 nm and 622 nm was taken as a measure of the amount of phosphorylated substrate. Data normalized (enzyme reaction without inhibitor = 0% inhibition, all other assay components except enzyme = 100% inhibition). Ten concentrations of test compounds on the same microtiter plate ranging from 20 μM to 1 nM (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9.2 nM, 3.1 nM and 1 nM) , 100-fold concentrated stock solutions are prepared in a series of 1: 3 dilutions to prepare a series of dilutions prior to the assay), multiple times at each concentration, and IC50 values are approximated to 4 parameters using in-house software Calculated by

Spindle assembly checkpoint assay The spindle assembly checkpoint ensures proper segregation of chromosomes during mitosis. Upon entering mitosis, the chromosome begins to condense with phosphorylation of histone H3 on serine 10. Dephosphorylation of histone H3 on serine 10 begins at late mitosis and ends at the end of mitosis. Thus, phosphorylation of histone H3 on serine 10 can be used as a marker for mitotic cells. Nocodazole is a microtubule unstable substance. Thus, nocodazole interferes with microtubule dynamics and triggers the spindle assembly checkpoint. Cells undergoing mitosis at the G2 / M transition are arrested and phosphorylated histone H3 is shown on serine 10. Inhibition of the spindle assembly checkpoint by Mps-1 inhibitor abolishes the blockage of cell division in the presence of nocodazole and the cells complete mitosis prematurely. This change is detected by cell loss due to phosphorylation of histone H3 on serine 10. This reduction is used as a marker to determine the ability of the compounds of the invention to induce mitotic breakthrough.

Cultured cells of the human uterine tumor cell line HeLa (ATCC CCL-2) were treated with 1% (v / v) glutamine, 1% (v / v) penicillin, 1% (v / v) streptomycin and 10% ( v / v) 2500 cells / in 384-well microtiter plates in 20 μl Dulbeco medium supplemented with fetal calf serum (W / O phenol red, W / O sodium pyruvate, w 1000 mg / ml glucose, w pyridoxine) It was seeded at the density of the well. After overnight incubation at 37 ° C., 10 μl / well nocodazole was added to the cells at a final concentration of 0.1 μg / ml. After 24 hours incubation, the cells were arrested at the G2 / M phase of cell cycle progression. Test compounds solubilized in dimethyl sulfoxide (DMSO) were added at various concentrations (0 μM, as well as in the range of 0.005 μM to 10 μM, the final concentration of solvent DMSO was 0.5% (v / v)) . The cells were incubated at 37 ° C. for 4 hours in the presence of the test compound. Cells were then fixed overnight in 4% (v / v) paraformaldehyde in phosphate buffered saline (PBS) at 4 ° C., and then 0.1% (V / V) Triton X (in PBS) Permeabilized for 20 minutes at room temperature in 100) and blocked in 0.5% (v / v) bovine serum albumin (BSA) in PBS for 15 minutes at room temperature. After washing with PBS, 20 μl / well antibody solution (anti-phosphorylated histone H3 clone 3H10, FITC; Upstate, catalog number 16-222, diluted 1: 200) was added to the cells and it was incubated at room temperature for 2 hours . The cells were then washed with PBS and 20 μl / well HOECHST 33342 dye solution (5 μg / ml) was added to the cells and the cells were incubated for 12 minutes at room temperature in the dark. Cells were washed twice with PBS, then covered with PBS and stored at 4 ° C. until analysis. Images were acquired with Perkin Elmer OPERA ™ High Content Analysis Reader. Images were analyzed with the image analysis software MetaXpress ™ from Molecular devices using the cell cycle application module. In this assay, both labeled Hoechst 33342 and phosphorylated histone H3 on serine 10 were measured. Hoechst 33342 is used to label the DNA and count the number of cells. Staining of phosphorylated histone H3 on serine 10 determines the number of mitotic cells. Inhibition of Mps-1 reduces the number of mitotic cells in the presence of nocodazole, indicating inappropriate mitotic progression. The raw assay data was further analyzed by 4-parameter logistic regression analysis to determine the IC ₅₀ value for each test compound.

  It will be apparent that assays for other Mps kinases can be similarly performed using appropriate reagents. Selected results are shown in the table below.

  Thus, the compounds of the present invention effectively inhibit one or more Mps-1 kinases and are therefore uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response In particular, diseases in which uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is mediated by Mps-1, particularly uncontrolled cells Growth, proliferation and / or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is a hematological tumor, solid tumor and / or metastasis thereof, eg leukemia and myelodysplastic syndrome, malignant lymphoma, brain tumor and brain metastasis Head and neck tumors, including non-small cell and small cell lung tumors, gastrointestinal tumors, endocrine tumors, breast tumors including mammary gland and other gynecological tumors, urological tumors including kidney tumors, bladder tumors and prostate tumors, skin Suitable for the treatment or prevention of tumors and sarcomas and / or diseases metastases thereof.

Claims (18)

Formula (I)

[Where:
R ¹ is C ₁ -C ₁₀ - alkyl -, halo -C ₁ -C ₁₀ - alkyl _{-, HO-C 1 -C 10} - alkyl -, C ₁ -C ₁₀ - alkoxy -C ₁ -C ₁₀ - alkyl - Aryloxy-C ₁ -C ₁₀ -alkyl-, halo-C ₁ -C ₁₀ -alkoxy-C ₁ -C ₁₀ -alkyl-, C ₂ -C ₁₀ -alkenyl-, C ₂ -C ₁₀ -alkynyl-, C ₃ -C ₁₀ - cycloalkyl -, 3-to 10-membered heterocycloalkyl -, aryl -, heteroaryl -, - C ₁ -C ₆ - alkylene -C ₃ -C ₁₀ - cycloalkyl, -C ₁ - C ₆ -alkylene- (3- to 10-membered heterocycloalkyl), -C ₁ -C ₆ -alkylene-aryl, -C ₁ -C ₆ -alkylene-heteroaryl groups,
Here, the following substituents optionally above groups: halo -, hydroxy -, cyano -, nitro -, C ₁ -C ₆ - alkyl -, halo -C ₁ -C ₆ - alkyl -, C ₁ -C ₆ -alkoxy-, halo-C ₁ -C ₆ -alkoxy-, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl -, C ₃ -C ₁₀ - cycloalkyl -, 3-to 10-membered heterocycloalkyl -, - C (= O) OH, -C (= O) OC 1 -C 6 - alkyl, -C (= O ) OC ₃ -C ₁₀ -cycloalkyl, -OC (= O) -C ₁ -C ₆ -alkyl, -OC (= O) -C ₃ -C ₁₀ -cycloalkyl, -N (H) C (= O ) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -N (H) S (= O) ₂ R ⁸ , -N (C ₁ -C ₆ -alkyl) S ( = O) ₂ R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -OC (= O) NR ⁹ R ¹⁰ , -N (H) C (= O) OR ⁸ , -N (C ₁ -C ₆ -Alkyl) C (= O) OR ⁸ , -N (H) C (= O) NR ⁹ R ¹⁰ , -N (C ₁ -C ₆ -alkyl) C (= O) NR ⁹ R ¹⁰ , -SR ^{8 , -S (= O) R 8} , -S (= O) 2 R 8, -S (= O) 2 NR 9 R 10, selected from -NR ⁹ R ^10, identical or different substituents Ri may be substituted one or more times,
R ² is an aryl- or heteroaryl- group, wherein said aryl- or heteroaryl-group is substituted once with —C (═O) NR ⁹ R ¹⁰ , and optionally halo-, Substituted with one substituent selected from hydroxy-, cyano-, C ₁ -C ₆ -alkyl-, halo-C ₁ -C ₆ -alkyl-,
R ³ , R ⁶ and R ⁷ are hydrogen atoms,
R ⁴ and R ⁵ are each independently a hydrogen atom, a halogen atom, a cyano- or a C ₁ -C ₆ -alkyl-group,
R ^8, R ^9, R ^10, independently of one another, hydrogen, C ₁ -C ₆ - alkyl -, halo -C ₁ -C ₆ - alkyl -, HO-C ₁ -C ₆ - alkyl -, cyano -C ₁ -C ₆ - alkyl -, C ₂ -C ₁₀ - alkynyl -C ₁ -C ₆ - alkyl -, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl -, halo -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl _{-, H 2 NC (= O} ) -C 1 -C 6 - alkyl -, C ₁ -C ₆ - alkyl -N (H) C (= O ) -C 1 -C ₆ - alkyl _{-, H 2 NS (= O} ) 2 -C 1 -C 6 - an alkyl -, C ₂ -C ₆ - alkenyl -, C ₂ -C ₆ - alkynyl -, C ₃ -C ₁₀ - cycloalkyl - , 3-to 10-membered heterocycloalkyl -, aryl, heteroaryl, - C ₁ -C ₆ - alkylene - aryl, -C ₁ -C ₆ - alkylene - heteroaryl, -C ₁ -C ₆ - alkylene -C _3- C ₁₀ -cycloalkyl, -C ₁ -C ₆ -alkylene-3- to 10-membered heterocycloalkyl group,
Or R ⁹ and R ¹⁰ together with the nitrogen to which they are attached are 3- to 10-membered heterocycloalkyl groups;
However,
R ¹ is
-CH ₂ CH ₂ CH ₂ OH,
-CH ₂ CH ₂ CH ₂ O (C = O) -R _a ,
-CH ₂ CH ₂ CH ₂ O (C = O) -OR _a ,
Not -CH ₂ CH ₂ CH ₂ O (C = O) -CHR _a NR _b R _c
Here, R _a, or different are R _b, R _c are the same, H, C ₁ -C ₁₀ - alkyl -, C ₂ -C ₁₀ - alkenyl -, C ₂ -C ₁₀ - alkynyl -, phenyl and Selected from the group consisting of heteroaryl]
Or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. R ¹ is C ₁ -C ₁₀ - alkyl -, halo -C ₁ -C ₁₀ - alkyl _{-, HO-C 1 -C 10} - alkyl -, C ₁ -C ₁₀ - alkoxy -C ₁ -C ₁₀ - alkyl - Aryloxy-C ₁ -C ₁₀ -alkyl-, halo-C ₁ -C ₁₀ -alkoxy-C ₁ -C ₁₀ -alkyl-, C ₂ -C ₁₀ -alkenyl-, C ₂ -C ₁₀ -alkynyl-, C ₃ -C ₁₀ - cycloalkyl -, 3-to 10-membered heterocycloalkyl -, aryl -, - C ₁ -C ₆ - alkylene -C ₃ -C ₁₀ - cycloalkyl, -C ₁ -C ₆ - alkylene - (3-to 10-membered heterocycloalkyl), - C ₁ -C ₆ - alkylene - aryl, -C ₁ -C ₆ - alkylene - a heteroaryl group,
Here, the following substituents optionally above groups: halo -, hydroxy -, cyano -, nitro -, C ₁ -C ₆ - alkyl -, halo -C ₁ -C ₆ - alkyl -, C ₁ -C ₆ -alkoxy-, halo-C ₁ -C ₆ -alkoxy-, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl -, C ₃ -C ₁₀ - cycloalkyl -, 3-to 10-membered heterocycloalkyl -, - C (= O) OH, -C (= O) OC 1 -C 6 - alkyl, -C (= O ) OC ₃ -C ₁₀ -cycloalkyl, -OC (= O) -C ₁ -C ₆ -alkyl, -OC (= O) -C ₃ -C ₁₀ -cycloalkyl, -N (H) C (= O ) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -N (H) S (= O) ₂ R ⁸ , -N (C ₁ -C ₆ -alkyl) S ( = O) ₂ R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -OC (= O) NR ⁹ R ¹⁰ , -N (H) C (= O) OR ⁸ , -N (C ₁ -C ₆ -Alkyl) C (= O) OR ⁸ , -N (H) C (= O) NR ⁹ R ¹⁰ , -N (C ₁ -C ₆ -alkyl) C (= O) NR ⁹ R ¹⁰ , -SR ^{8 , -S (= O) R 8} , -S (= O) 2 R 8, -S (= O) 2 NR 9 R 10, selected from -NR ⁹ R ^10, identical or different substituents Ri may be substituted one or more times,
R ² is an aryl- or heteroaryl- group, wherein said aryl- or heteroaryl-group is substituted once with —C (═O) NH-cyclopropyl, and optionally halo-, Substituted with one substituent selected from hydroxy-, cyano-, C ₁ -C ₆ -alkyl-, halo-C ₁ -C ₆ -alkyl-,
R ³ , R ⁶ and R ⁷ are hydrogen atoms,
R ⁴ and R ⁵ are independently of each other a hydrogen atom, a halogen atom, a cyano- or a C ₁ -C ₆ -alkyl-group ,
R ^8, R ^9, R ¹⁰ each independently represent hydrogen, C ₁ -C ₆ - alkyl -, halo -C ₁ -C ₆ - alkyl _{-, HO-C 1 -C 6} - alkyl -, cyano - C ₁ -C ₆ - alkyl -, C ₂ -C ₁₀ - alkynyl -C ₁ -C ₆ - alkyl -, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl -, halo -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl _{-, H 2 NC (= O} ) -C 1 -C 6 - alkyl -, C ₁ -C ₆ - alkyl -N (H) C (= O ) -C 1 - C ₆ - alkyl _{-, H 2 NS (= O} ) 2 -C 1 -C 6 - alkyl -, C ₂ -C ₆ - alkenyl -, C ₂ -C ₆ - alkynyl -, C ₃ -C ₁₀ - cycloalkyl -, 3-to 10-membered heterocycloalkyl -, aryl, heteroaryl, - C ₁ -C ₆ - alkylene - aryl, -C ₁ -C ₆ - alkylene - heteroaryl, -C ₁ -C ₆ - alkylene - C ₃ -C ₁₀ - alkylene -3-to 10-membered heterocycloalkyl group, - cycloalkyl, -C ₁ -C ₆
Or R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached are 3- to 10-membered heterocycloalkyl groups;
However,
R ¹ is
-CH ₂ CH ₂ CH ₂ OH,
-CH ₂ CH ₂ CH ₂ O (C = O) -R _a ,
-CH ₂ CH ₂ CH ₂ O (C = O) -OR _a ,
-CH ₂ CH ₂ CH ₂ O (C = O) -CHR _a NR _b R _c ,
Here, R _a, or different are R _b, R _c are the same, H, C ₁ -C ₁₀ - alkyl -, C ₂ -C ₁₀ - alkenyl -, C ₂ -C ₁₀ - alkynyl -, phenyl and The compound according to claim 1 selected from the group consisting of heteroaryl, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. R ¹ is C ₁ -C ₁₀ - alkyl -, halo -C ₁ -C ₁₀ - alkyl _{-, HO-C 1 -C 10} - alkyl -, C ₁ -C ₁₀ - alkoxy -C ₁ -C ₁₀ - alkyl - Aryloxy-C ₁ -C ₁₀ -alkyl-, halo-C ₁ -C ₁₀ -alkoxy-C ₁ -C ₁₀ -alkyl-, C ₂ -C ₁₀ -alkenyl-, C ₂ -C ₁₀ -alkynyl-, C ₃ -C ₁₀ - cycloalkyl -, 3-to 10-membered heterocycloalkyl -, aryl -, - C ₁ -C ₆ - alkylene -C ₃ -C ₁₀ - cycloalkyl, -C ₁ -C ₆ - alkylene - (3-to 10-membered heterocycloalkyl), - C ₁ -C ₆ - alkylene - aryl, -C ₁ -C ₆ - alkylene - a heteroaryl group,
Here, the following substituents optionally above groups: halo -, hydroxy -, cyano -, nitro -, C ₁ -C ₆ - alkyl -, halo -C ₁ -C ₆ - alkyl -, C ₁ -C ₆ -alkoxy-, halo-C ₁ -C ₆ -alkoxy-, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl-, halo-C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl -, C ₃ -C ₁₀ - cycloalkyl -, 3-to 10-membered heterocycloalkyl -, - C (= O) OH, -C (= O) OC 1 -C 6 - alkyl, -C (= O ) OC ₃ -C ₁₀ -cycloalkyl, -OC (= O) -C ₁ -C ₆ -alkyl, -OC (= O) -C ₃ -C ₁₀ -cycloalkyl, -N (H) C (= O ) R ⁸ , -N (C ₁ -C ₆ -alkyl) C (= O) R ⁸ , -N (H) S (= O) ₂ R ⁸ , -N (C ₁ -C ₆ -alkyl) S ( = O) ₂ R ⁸ , -C (= O) NR ⁹ R ¹⁰ , -OC (= O) NR ⁹ R ¹⁰ , -N (H) C (= O) OR ⁸ , -N (C ₁ -C ₆ -Alkyl) C (= O) OR ⁸ , -N (H) C (= O) NR ⁹ R ¹⁰ , -N (C ₁ -C ₆ -alkyl) C (= O) NR ⁹ R ¹⁰ , -SR ^{8 , -S (= O) R 8} , -S (= O) 2 R 8, -S (= O) 2 NR 9 R 10, selected from -NR ⁹ R ^10, identical or different substituents Ri may be substituted one or more times,
R ² is an aryl- or heteroaryl- group, wherein said aryl- or heteroaryl-group is substituted once with —C (═O) NH-cyclopropyl, and optionally substituted May be substituted by one substituent selected from the group: halo-, hydroxy-, cyano-, C ₁ -C ₆ -alkyl-, halo-C ₁ -C ₆ -alkyl-,
R ³ , R ⁶ and R ⁷ are hydrogen atoms,
R ⁴ and R ⁵ are each independently a hydrogen atom, a halogen atom, cyano- or C ₁ -C ₆ -alkyl- ;
R ^8, R ^9, R ^10, independently of one another, hydrogen, C ₁ -C ₆ - alkyl -, halo -C ₁ -C ₆ - alkyl -, HO-C ₁ -C ₆ - alkyl -, cyano -C ₁ -C ₆ - alkyl -, C ₂ -C ₁₀ - alkynyl -C ₁ -C ₆ - alkyl -, C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl -, halo -C ₁ -C ₆ - alkoxy -C ₁ -C ₆ - alkyl _{-, H 2 NC (= O} ) -C 1 -C 6 - alkyl -, C ₁ -C ₆ - alkyl -N (H) C (= O ) -C 1 -C ₆ - alkyl _{-, H 2 NS (= O} ) 2 -C 1 -C 6 - an alkyl -, C ₂ -C ₆ - alkenyl -, C ₂ -C ₆ - alkynyl -, C ₃ -C ₁₀ - cycloalkyl - , 3-to 10-membered heterocycloalkyl -, aryl, heteroaryl, - C ₁ -C ₆ - alkylene - aryl, -C ₁ -C ₆ - alkylene - heteroaryl, -C ₁ -C ₆ - alkylene -C _3- C ₁₀ -cycloalkyl, -C ₁ -C ₆ -alkylene-3- to 10-membered heterocycloalkyl group,
Or R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached are 3- to 10-membered heterocycloalkyl groups;
However,
R ¹ is
-CH ₂ CH ₂ CH ₂ OH,
-CH ₂ CH ₂ CH ₂ O (C = O) -R _a ,
-CH ₂ CH ₂ CH ₂ O (C = O) -OR _a ,
-CH ₂ CH ₂ CH ₂ O (C = O) -CHR _a NR _b R _c ,
R _a, R _b, or different R _c is the same, H, C ₁ -C ₁₀ - alkyl -, C ₂ -C ₁₀ - alkenyl -, C ₂ -C ₁₀ - alkynyl -, phenyl and heteroaryl The compound according to claim 1 or 2 selected from the group consisting of the following, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. 1-ethyl-3- [4- (4-isobutylamino-imidazo [1,2-a] quinoxalin-1-yl) -phenyl] -urea,
1- (2-fluorophenyl) -N- (2-methylpropyl) imidazo [1,2-a] quinoxalin-4-amine,
1- (4-methoxy-2-methylphenyl) -N- (2-methylpropyl) imidazo [1,2-a] quinoxalin-4-amine,
1- (2,5-difluorophenyl) -N- (2-methylpropyl) imidazo [1,2-a] quinoxalin-4-amine,
N-cyclopropyl-4- {4-[(3-methylbutyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
4- [4- (benzylamino) imidazo [1,2-a] quinoxalin-1-yl] -N-cyclopropylbenzamide,
4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N- [2- (2-oxoimidazolidin-1-yl) ethyl] benzamide,
N- [2- (methylamino) -2-oxoethyl] -4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N- [2- (pyridin-3-yl) ethyl] benzamide,
N- {4-[(4-Methylpiperazin-1-yl) methyl] -3- (trifluoromethyl) phenyl} -4- {4-[(2-methylpropyl) amino] imidazo [1,2-a Quinoxalin-1-yl} benzamide,
N- (1-methylcyclopropyl) -4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzoic acid,
1- (2-fluoropyridin-3-yl) -N- (2-methylpropyl) imidazo [1,2-a] quinoxalin-4-amine,
4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
1- (2,3-difluorophenyl) -N- (2-methylpropyl) imidazo [1,2-a] quinoxalin-4-amine,
1- (3-fluoro-4-methoxyphenyl) -N- (2-methylpropyl) imidazo [1,2-a] quinoxalin-4-amine,
N- (2-methylpropyl) -1- (5-methylthiophen-2-yl) imidazo [1,2-a] quinoxalin-4-amine,
N- (2-methylpropyl) -1- (6-methylpyridin-3-yl) imidazo [1,2-a] quinoxalin-4-amine,
2-chloro-N-cyclopropyl-4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-methyl-5- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} pyridine-2-carboxamide;
N-cyclopropyl-4- {4-[(4-sulfamoylbenzyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- (4-{[2- (pyridin-3-yl) ethyl] amino} imidazo [1,2-a] quinoxalin-1-yl) benzamide,
N-cyclopropyl-4- {4-[(2-sulfamoylethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-propylbenzamide,
N- (2-hydroxyethyl) -4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N- (4-sulfamoylphenyl) benzamide,
4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N- [1- (pyridin-2-yl) cyclopropyl] benzamide,
1- [4- (4-Isobutylamino-imidazo [1,2-a] quinoxalin-1-yl) -phenyl] -3- [4- (4-methyl-piperazin-1-ylmethyl) -3-trifluoro Methyl-phenyl] -urea,
1- (2,3-dihydro-1,4-benzodioxin-6-yl) -N- (2-methylpropyl) imidazo [1,2-a] quinoxalin-4-amine,
1- (2-fluoro-3-methoxyphenyl) -N- (2-methylpropyl) imidazo [1,2-a] quinoxalin-4-amine,
N- (2-methylpropyl) -1- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-a] quinoxalin-4-amine,
1- (1,3-benzodioxol-5-yl) -N- (2-methylpropyl) imidazo [1,2-a] quinoxalin-4-amine,
3- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenol,
1- (1H-indol-5-yl) -N- (2-methylpropyl) imidazo [1,2-a] quinoxalin-4-amine,
2-chloro-N-methyl-4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- {4-[(3-fluorobenzyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- {4-[(2-methylbenzyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- (4-{[2- (morpholin-4-yl) ethyl] amino} imidazo [1,2-a] quinoxalin-1-yl) benzamide;
N-cyclopropyl-4- (4-{[2- (2-oxoimidazolidin-1-yl) ethyl] amino} imidazo [1,2-a] quinoxalin-1-yl) benzamide;
4- {4-[(4-cyanobenzyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
N-cyclopropyl-4- {4-[(1-methyl-1H-pyrazol-3-yl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N- [3- (2-oxopyrrolidin-1-yl) propyl] benzamide,
N- (3-carbamoylphenyl) -4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N- (1-methyl-1H-pyrazol-3-yl) benzamide,
N- {3-[(4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzoyl) amino] phenyl} pyridine-3-carboxamide;
1- (4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) ethanone,
1- (1H-indazol-5-yl) -N- (2-methylpropyl) imidazo [1,2-a] quinoxalin-4-amine,
N-cyclopropyl-4- [4- (2-hydroxy-ethylamino) -imidazo [1,2-a] quinoxalin-1-yl] -benzamide,
N-cyclopropyl-4- {4-[(3-methylbenzyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- {4-[(2-methoxybenzyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- [4- (ethylamino) imidazo [1,2-a] quinoxalin-1-yl] benzamide,
N-cyclopropyl-4- [4-({4-[(methylsulfonyl) amino] phenyl} amino) imidazo [1,2-a] quinoxalin-1-yl] benzamide,
N- (1-benzylpiperidin-4-yl) -4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N- {3-[(4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzoyl) amino] phenyl} pyridine-4-carboxamide;
N- (2-methylpropyl) -1- [4- (methylsulfonyl) phenyl] imidazo [1,2-a] quinoxalin-4-amine,
1- (1H-indazol-6-yl) -N- (2-methylpropyl) imidazo [1,2-a] quinoxalin-4-amine,
N-cyclopropyl-4- (4-{[3- (morpholin-4-yl) propyl] amino} imidazo [1,2-a] quinoxalin-1-yl) benzamide;
N-cyclopropyl-4- {4-[(2-methoxyethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- (4-{[2- (4-methoxyphenyl) ethyl] amino} imidazo [1,2-a] quinoxalin-1-yl) benzamide,
N-cyclopropyl-4- {4-[(thiophen-2-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide;
N-cyclopropyl-4- (4-{[2- (4-sulfamoylphenyl) ethyl] amino} imidazo [1,2-a] quinoxalin-1-yl) benzamide,
N-cyclopropyl-4- {4-[(2-phenoxyethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N, N-diethyl-4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N- (1-hydroxypropan-2-yl) -4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N- (2-methylcyclopropyl) -4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N- [1- (hydroxymethyl) cyclopropyl] -4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- (4-isobutylamino-imidazo [1,2-a] quinoxalin-1-yl) -benzamide,
1- (4-methylphenyl) -N- (2-methylpropyl) imidazo [1,2-a] quinoxalin-4-amine,
N- (2-methylpropyl) -1- [4- (methylsulfanyl) phenyl] imidazo [1,2-a] quinoxalin-4-amine,
1- (2-methylphenyl) -N- (2-methylpropyl) imidazo [1,2-a] quinoxalin-4-amine,
1- (1H-indol-6-yl) -N- (2-methylpropyl) imidazo [1,2-a] quinoxalin-4-amine,
1- (isoquinolin-5-yl) -N- (2-methylpropyl) imidazo [1,2-a] quinoxalin-4-amine,
N-methyl-3- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N- (2-methylpropyl) -1- [2- (trifluoromethyl) phenyl] imidazo [1,2-a] quinoxalin-4-amine,
4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenol,
1- (2-fluoro-4-methylphenyl) -N- (2-methylpropyl) imidazo [1,2-a] quinoxalin-4-amine,
4- {4-[(3-chlorobenzyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
N-cyclopropyl-4- {4-[(2-phenylethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- [4- (phenylamino) imidazo [1,2-a] quinoxalin-1-yl] benzamide,
N-cyclopropyl-4- {4-[(cyclopropylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- {4-[(pyridin-3-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide;
N-cyclopropyl-4- (4-{[4- (pyrrolidin-1-yl) butyl] amino} imidazo [1,2-a] quinoxalin-1-yl) benzamide,
N-cyclopropyl-4- (4-{[2- (4-fluorophenyl) ethyl] amino} imidazo [1,2-a] quinoxalin-1-yl) benzamide;
4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N- (1H-pyrazol-3-yl) benzamide,
4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N- (prop-2-in-1-yl) benzamide,
4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N- [2- (pyridin-4-yl) ethyl] benzamide,
1-ethyl-N- {3-[(4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzoyl) amino] phenyl} -1H-pyrazole- 5-carboxamide,
N- (2-methylpropyl) -1-phenylimidazo [1,2-a] quinoxalin-4-amine,
N-methyl-4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N- (2-methylpropyl) -1- (thiophen-2-yl) imidazo [1,2-a] quinoxalin-4-amine,
1- (4-ethoxyphenyl) -N- (2-methylpropyl) imidazo [1,2-a] quinoxalin-4-amine,
N- (2-methylpropyl) -1- (pyridin-3-yl) imidazo [1,2-a] quinoxalin-4-amine,
N- (2-methylpropyl) -1- (pyridin-4-yl) imidazo [1,2-a] quinoxalin-4-amine,
N- (3- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzyl) acetamide,
N-cyclopropyl-4- [4- (pentylamino) imidazo [1,2-a] quinoxalin-1-yl] benzamide,
N-cyclopropyl-4- (4-{[3- (2-oxopyrrolidin-1-yl) propyl] amino} imidazo [1,2-a] quinoxalin-1-yl) benzamide;
N-cyclopropyl-4- {4-[(2-fluorobenzyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- (4-{[2- (3-fluorophenyl) ethyl] amino} imidazo [1,2-a] quinoxalin-1-yl) benzamide;
4- {4-[(1,3-benzodioxol-5-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
N-ethyl-4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N- (2-carbamoylphenyl) -4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N- [3- (acetylamino) phenyl] -4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N- (2-fluorocyclopropyl) -4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N, N-dimethyl-4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
1- (2-methoxypyrimidin-5-yl) -N- (2-methylpropyl) imidazo [1,2-a] quinoxalin-4-amine,
(4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) (pyrrolidin-1-yl) methanone,
N- (2-methylpropyl) -1- (thiophen-3-yl) imidazo [1,2-a] quinoxalin-4-amine,
1- (3,4-dimethoxyphenyl) -N- (2-methylpropyl) imidazo [1,2-a] quinoxalin-4-amine,
(4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) methanol,
2- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenol,
N- (2-methylpropyl) -1- (1H-pyrazol-3-yl) imidazo [1,2-a] quinoxalin-4-amine,
N-cyclopropyl-4- {4-[(4-fluorobenzyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- (4-{[3- (dimethylamino) propyl] amino} imidazo [1,2-a] quinoxalin-1-yl) benzamide;
N-cyclopropyl-4- {4-[(3-phenylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- (4-{[2- (pyridin-4-yl) ethyl] amino} imidazo [1,2-a] quinoxalin-1-yl) benzamide;
4-({1- [4- (cyclopropylcarbamoyl) phenyl] imidazo [1,2-a] quinoxalin-4-yl} amino) -3-methoxy-N- (1-methylpiperidin-4-yl) benzamide ,
N- (2-amino-2-oxoethyl) -4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N- (3-amino-3-oxopropyl) -4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N- (1-cyanocyclopropyl) -4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
4- {4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N- (2-sulfamoylethyl) benzamide,
N-cyclopropyl-4- [8-fluoro-4- (propylamino) imidazo [1,2-a] quinoxalin-1-yl] benzamide,
N-cyclopropyl-4- {8-fluoro-4-[(pyridin-3-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide;
N-cyclopropyl-4- {8-fluoro-4-[(3-methoxypropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- {7,8-difluoro-4-[(3-methylbutyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide;
N-cyclopropyl-4- (7,8-difluoro-4-{[(1-methyl-1H-pyrazol-4-yl) methyl] amino} imidazo [1,2-a] quinoxalin-1-yl) benzamide ,
1- (4- {7,8-difluoro-4-[(3-hydroxypropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
N- {2-[(7,8-difluoro-1- {4-[(methylcarbamoyl) amino] phenyl} imidazo [1,2-a] quinoxalin-4-yl) amino] ethyl} acetamide,
2-chloro-N-cyclopropyl-4- {7,8-difluoro-4-[(2-fluorobenzyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
2-chloro-N-cyclopropyl-4- {7,8-difluoro-4-[(3-hydroxypropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
tert-butyl [3-({1- [3-chloro-4- (cyclopropylcarbamoyl) phenyl] -7,8-difluoroimidazo [1,2-a] quinoxalin-4-yl} amino) propyl] carbamate,
N-cyclopropyl-4- [4- (ethylamino) -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl] benzamide,
N-cyclopropyl-4- {7,8-dimethyl-4-[(pyridin-2-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide;
N-cyclopropyl-4- {4-[(2,3-dihydroxypropyl) amino] -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl} benzamide,
1- (4- {4-[(2-methoxyethyl) amino] -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
2-chloro-N-cyclopropyl-4- {4-[(2-hydroxyethyl) amino] -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl} benzamide,
2-Chloro-N-cyclopropyl-4- (4-{[3- (1H-imidazol-1-yl) propyl] amino} -7, 8-dimethylimidazo [1,2-a] quinoxalin-1-yl Benzamide,
2-chloro-N-cyclopropyl-4- {4-[(cyclopropylmethyl) amino] -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl} benzamide,
2-chloro-N-cyclopropyl-4- {7,8-dimethyl-4-[(pyridin-3-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
4- {4-[(3-amino-3-oxopropyl) amino] -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl} -2-chloro-N-cyclopropylbenzamide,
tert-butyl [3-({1- [3-chloro-4- (cyclopropylcarbamoyl) phenyl] -7-cyanoimidazo [1,2-a] quinoxalin-4-yl} amino) propyl] carbamate,
N-cyclopropyl-4- {8-fluoro-4-[(thiophen-2-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide;
N-cyclopropyl-4- [4- (ethylamino) -8-fluoroimidazo [1,2-a] quinoxalin-1-yl] benzamide,
4- [4- (butylamino) -8-fluoroimidazo [1,2-a] quinoxalin-1-yl] -N-cyclopropylbenzamide,
1- (4- {8-fluoro-4-[(2-methoxyethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
1- (4- {8-fluoro-4-[(4-hydroxybutyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
1- [4- (8-Fluoro-4-{[(1-methyl-1H-pyrazol-4-yl) methyl] amino} imidazo [1,2-a] quinoxalin-1-yl) phenyl] -3- Methylurea,
2-chloro-N-cyclopropyl-4- [8-fluoro-4- (propylamino) imidazo [1,2-a] quinoxalin-1-yl] benzamide,
2-chloro-N-cyclopropyl-4- {8-fluoro-4-[(pyridin-4-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- {7,8-difluoro-4-[(2-methoxyethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide;
N-cyclopropyl-4- {7,8-difluoro-4-[(3-hydroxypropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide;
N-cyclopropyl-4- {7,8-difluoro-4-[(furan-2-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide;
N-cyclopropyl-4- {7,8-difluoro-4-[(3-methoxypropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
1- {4- [7,8-difluoro-4- (propylamino) imidazo [1,2-a] quinoxalin-1-yl] phenyl} -3-methylurea,
4- [4- (butylamino) -7,8-difluoroimidazo [1,2-a] quinoxalin-1-yl] -2-chloro-N-cyclopropylbenzamide,
2-chloro-N-cyclopropyl-4- {7,8-difluoro-4-[(2-sulfamoylethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
1- {4- [4- (benzylamino) -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl] phenyl} -3-methylurea,
1- (4- {7,8-dimethyl-4-[(pyridin-4-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
1- (4- {7,8-dimethyl-4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
4- (7-cyano-4-{[3- (morpholin-4-yl) propyl] amino} imidazo [1,2-a] quinoxalin-1-yl) -N-cyclopropylbenzamide,
4- (7-cyano-4-{[3- (2-oxopyrrolidin-1-yl) propyl] amino} imidazo [1,2-a] quinoxalin-1-yl) -N-cyclopropylbenzamide,
1- [4- (7-cyano-4-{[3- (2-oxopyrrolidin-1-yl) propyl] amino} imidazo [1,2-a] quinoxalin-1-yl) phenyl] -3-methylurea ,
2-chloro-4- {7-cyano-4-[(4-hydroxybutyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
2-chloro-4- {7-cyano-4-[(3-methoxypropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
N-cyclopropyl-4- {8-fluoro-4-[(2-methoxyethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
1- (4- {8-fluoro-4-[(2,2,2-trifluoroethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
1- [4- (8-fluoro-4-{[3- (1H-imidazol-1-yl) propyl] amino} imidazo [1,2-a] quinoxalin-1-yl) phenyl] -3-methylurea,
2-chloro-N-cyclopropyl-4- {8-fluoro-4-[(3-hydroxypropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
2-chloro-N-cyclopropyl-4- {8-fluoro-4-[(3-methoxypropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- (7,8-difluoro-4-{[3- (morpholin-4-yl) propyl] amino} imidazo [1,2-a] quinoxalin-1-yl) benzamide;
N-cyclopropyl-4- {7,8-difluoro-4-[(4-fluorobenzyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide;
1- (4- {7,8-difluoro-4-[(pyridin-3-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
2-Chloro-N-cyclopropyl-4- (7,8-difluoro-4-{[3- (2-oxopyrrolidin-1-yl) propyl] amino} imidazo [1,2-a] quinoxaline-1- Il) benzamide,
2-chloro-N-cyclopropyl-4- {7,8-difluoro-4-[(pyridin-4-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide;
4- [4- (butylamino) -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl] -N-cyclopropylbenzamide,
N-cyclopropyl-4- {4-[(furan-2-ylmethyl) amino] -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl} benzamide,
1- {4- [4- (ethylamino) -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl] phenyl} -3-methylurea,
2-Chloro-N-cyclopropyl-4- (7,8-dimethyl-4-{[3- (morpholin-4-yl) propyl] amino} imidazo [1,2-a] quinoxalin-1-yl) benzamide ,
2-Chloro-N-cyclopropyl-4- (7,8-dimethyl-4-{[3- (2-oxopyrrolidin-1-yl) propyl] amino} imidazo [1,2-a] quinoxaline-1- Il) benzamide,
4- [4- (butylamino) -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl] -2-chloro-N-cyclopropylbenzamide,
2-chloro-N-cyclopropyl-4- {7,8-dimethyl-4-[(pyridin-2-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide;
2-Chloro-N-cyclopropyl-4- (7,8-dimethyl-4-{[(1-methyl-1H-pyrazol-4-yl) methyl] amino} imidazo [1,2-a] quinoxaline-1 -Il) benzamide,
4- [7-cyano-4- (propylamino) imidazo [1,2-a] quinoxalin-1-yl] -N-cyclopropylbenzamide,
4- {7-cyano-4-[(2-methoxyethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
4- [7-cyano-4- (ethylamino) imidazo [1,2-a] quinoxalin-1-yl] -N-cyclopropylbenzamide,
4- {7-cyano-4-[(3-hydroxypropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
4- [4- (butylamino) -7-cyanoimidazo [1,2-a] quinoxalin-1-yl] -N-cyclopropylbenzamide,
4- {7-cyano-4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
2-chloro-4- {7-cyano-4-[(3-hydroxypropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
4- (4-{[2- (acetylamino) ethyl] amino} -7-cyanoimidazo [1,2-a] quinoxalin-1-yl) -2-chloro-N-cyclopropylbenzamide,
2-chloro-4- {7-cyano-4-[(pyridin-4-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
1- (4- {8-fluoro-4-[(2-fluorobenzyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
1- (4- {8-fluoro-4-[(3-methoxypropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
2-Chloro-N-cyclopropyl-4- (8-fluoro-4-{[(1-methyl-1H-pyrazol-4-yl) methyl] amino} imidazo [1,2-a] quinoxalin-1-yl Benzamide,
N-cyclopropyl-4- [4- (ethylamino) -7,8-difluoroimidazo [1,2-a] quinoxalin-1-yl] benzamide,
4- (4-{[2- (acetylamino) ethyl] amino} -7,8-difluoroimidazo [1,2-a] quinoxalin-1-yl) -N-cyclopropylbenzamide,
1- (4- {7,8-difluoro-4-[(pyridin-4-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
4- (4-{[2- (acetylamino) ethyl] amino} -7,8-difluoroimidazo [1,2-a] quinoxalin-1-yl) -2-chloro-N-cyclopropylbenzamide,
2-Chloro-N-cyclopropyl-4- (7,8-difluoro-4-{[3- (1H-imidazol-1-yl) propyl] amino} imidazo [1,2-a] quinoxalin-1-yl Benzamide,
2-chloro-N-cyclopropyl-4- {7,8-difluoro-4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
2-Chloro-N-cyclopropyl-4- (7,8-difluoro-4-{[(1-methyl-1H-pyrazol-4-yl) methyl] amino} imidazo [1,2-a] quinoxaline-1 -Il) benzamide,
1- {4- [7,8-dimethyl-4- (propylamino) imidazo [1,2-a] quinoxalin-1-yl] phenyl} -3-methylurea,
1- [4- (7,8-dimethyl-4-{[3- (morpholin-4-yl) propyl] amino} imidazo [1,2-a] quinoxalin-1-yl) phenyl] -3-methylurea,
1- [4- (4-{[3- (1H-imidazol-1-yl) propyl] amino} -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl) phenyl] -3- Methylurea,
2-chloro-N-cyclopropyl-4- {7,8-dimethyl-4-[(3-methylbutyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
2-Chloro-N-cyclopropyl-4- (7,8-dimethyl-4-{[(1-methyl-1H-pyrazol-5-yl) methyl] amino} imidazo [1,2-a] quinoxaline-1 -Il) benzamide,
2-chloro-N-cyclopropyl-4- {4-[(2,3-dihydroxypropyl) amino] -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl} benzamide,
4- {7-cyano-4-[(3-fluorobenzyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
4- {4-[(3-amino-3-oxopropyl) amino] -7-cyanoimidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
4- (7-cyano-4-{[(1-methyl-1H-pyrazol-5-yl) methyl] amino} imidazo [1,2-a] quinoxalin-1-yl) -N-cyclopropylbenzamide,
1- (4- {7-cyano-4-[(pyridin-3-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
4- [4- (butylamino) -7-cyanoimidazo [1,2-a] quinoxalin-1-yl] -2-chloro-N-cyclopropylbenzamide,
2-chloro-4- {7-cyano-4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
N-cyclopropyl-4- {8-fluoro-4-[(2-hydroxyethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- {8-fluoro-4-[(3-methylbutyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- (8-fluoro-4-{[3- (2-oxopyrrolidin-1-yl) propyl] amino} imidazo [1,2-a] quinoxalin-1-yl) benzamide;
N-cyclopropyl-4- {8-fluoro-4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
4- {4-[(3-amino-3-oxopropyl) amino] -8-fluoroimidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
N-cyclopropyl-4- [7,8-difluoro-4- (propylamino) imidazo [1,2-a] quinoxalin-1-yl] benzamide,
4- [4- (butylamino) -7,8-difluoroimidazo [1,2-a] quinoxalin-1-yl] -N-cyclopropylbenzamide,
N-cyclopropyl-4- (7,8-difluoro-4-{[3- (1H-imidazol-1-yl) propyl] amino} imidazo [1,2-a] quinoxalin-1-yl) benzamide;
N-cyclopropyl-4- {4-[(cyclopropylmethyl) amino] -7,8-difluoroimidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- (7,8-difluoro-4-{[(1-methyl-1H-pyrazol-5-yl) methyl] amino} imidazo [1,2-a] quinoxalin-1-yl) benzamide ,
1- [4- (7,8-Difluoro-4-{[3- (2-oxopyrrolidin-1-yl) propyl] amino} imidazo [1,2-a] quinoxalin-1-yl) phenyl] -3 -Methylurea,
1- (4- {7,8-difluoro-4-[(pyridin-2-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
2-chloro-N-cyclopropyl-4- {7,8-difluoro-4-[(pyridin-3-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
4- {4-[(3-amino-3-oxopropyl) amino] -7,8-difluoroimidazo [1,2-a] quinoxalin-1-yl} -2-chloro-N-cyclopropylbenzamide,
N-cyclopropyl-4- [7,8-dimethyl-4- (propylamino) imidazo [1,2-a] quinoxalin-1-yl] benzamide,
N-cyclopropyl-4- {4-[(cyclopropylmethyl) amino] -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- {7,8-dimethyl-4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N ^Three -(7,8-dimethyl-1- {4-[(methylcarbamoyl) amino] phenyl} imidazo [1,2-a] quinoxalin-4-yl) -beta-alaninamide,
1- [4- (7,8-dimethyl-4-{[(1-methyl-1H-pyrazol-4-yl) methyl] amino} imidazo [1,2-a] quinoxalin-1-yl) phenyl]- 3-methylurea,
2-chloro-N-cyclopropyl-4- {4-[(4-hydroxybutyl) amino] -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl} benzamide,
tert-butyl [3-({1- [3-chloro-4- (cyclopropylcarbamoyl) phenyl] -7,8-dimethylimidazo [1,2-a] quinoxalin-4-yl} amino) propyl] carbamate,
4- {7-cyano-4-[(2,2,2-trifluoroethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
4- {7-cyano-4-[(pyridin-2-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
1- (4- {7-cyano-4-[(3-hydroxypropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
1- (4- {7-cyano-4-[(2,3-dihydroxypropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
2-chloro-4- {7-cyano-4-[(3-methylbutyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
2-chloro-4- {7-cyano-4-[(2-fluorobenzyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
2-Chloro-4- (7-cyano-4-{[(1-methyl-1H-pyrazol-4-yl) methyl] amino} imidazo [1,2-a] quinoxalin-1-yl) -N-cyclo Propylbenzamide,
1- (4- {4-[(2,3-dihydroxypropyl) amino] -8-fluoroimidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
2-chloro-N-cyclopropyl-4- {8-fluoro-4-[(2-methoxyethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
2-chloro-N-cyclopropyl-4- {4-[(2,3-dihydroxypropyl) amino] -8-fluoroimidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- {7,8-difluoro-4-[(thiophen-2-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide;
N-cyclopropyl-4- (7,8-difluoro-4-{[(1-methyl-1H-pyrazol-3-yl) methyl] amino} imidazo [1,2-a] quinoxalin-1-yl) benzamide ,
1- [4- (7,8-Difluoro-4-{[3- (1H-imidazol-1-yl) propyl] amino} imidazo [1,2-a] quinoxalin-1-yl) phenyl] -3- Methylurea,
1- (4- {4-[(cyclopropylmethyl) amino] -7,8-difluoroimidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
2-chloro-N-cyclopropyl-4- {7,8-difluoro-4-[(3-methoxypropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- (7,8-dimethyl-4-{[(1-methyl-1H-pyrazol-4-yl) methyl] amino} imidazo [1,2-a] quinoxalin-1-yl) benzamide ,
1- (4- {4-[(3-fluorobenzyl) amino] -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
1- (4- {4-[(2-fluorobenzyl) amino] -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
2-[(7,8-dimethyl-1- {4-[(methylcarbamoyl) amino] phenyl} imidazo [1,2-a] quinoxalin-4-yl) amino] ethanesulfonamide,
2-chloro-N-cyclopropyl-4- [7,8-dimethyl-4- (propylamino) imidazo [1,2-a] quinoxalin-1-yl] benzamide,
2-chloro-N-cyclopropyl-4- {4-[(3-hydroxypropyl) amino] -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl} benzamide,
4- (4-{[2- (acetylamino) ethyl] amino} -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl) -2-chloro-N-cyclopropylbenzamide,
2-chloro-N-cyclopropyl-4- {7,8-dimethyl-4-[(pyridin-4-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide;
2-chloro-N-cyclopropyl-4- {7,8-dimethyl-4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
2-Chloro-N-cyclopropyl-4- (7,8-dimethyl-4-{[(1-methyl-1H-pyrazol-3-yl) methyl] amino} imidazo [1,2-a] quinoxaline-1 -Il) benzamide,
4- (7-cyano-4-{[(1-methyl-1H-pyrazol-4-yl) methyl] amino} imidazo [1,2-a] quinoxalin-1-yl) -N-cyclopropylbenzamide,
N- {2-[(7-cyano-1- {4-[(methylcarbamoyl) amino] phenyl} imidazo [1,2-a] quinoxalin-4-yl) amino] ethyl} acetamide,
2-chloro-4- {7-cyano-4-[(2-hydroxyethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
2-chloro-4- {7-cyano-4-[(pyridin-3-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
2-Chloro-4- (7-cyano-4-{[(1-methyl-1H-pyrazol-3-yl) methyl] amino} imidazo [1,2-a] quinoxalin-1-yl) -N-cyclo Propylbenzamide,
2-chloro-4- {7-cyano-4-[(2,3-dihydroxypropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
N-cyclopropyl-4- {8-fluoro-4-[(4-fluorobenzyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- {8-fluoro-4-[(3-hydroxypropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- {8-fluoro-4-[(pyridin-2-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide;
N-cyclopropyl-4- {4-[(2,3-dihydroxypropyl) amino] -8-fluoroimidazo [1,2-a] quinoxalin-1-yl} benzamide;
1- (4- {8-fluoro-4-[(3-hydroxypropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
1- (4- {8-fluoro-4-[(pyridin-3-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
1- (4- {8-fluoro-4-[(furan-2-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
2-[(8-fluoro-1- {4-[(methylcarbamoyl) amino] phenyl} imidazo [1,2-a] quinoxalin-4-yl) amino] ethanesulfonamide,
2-chloro-N-cyclopropyl-4- (8-fluoro-4-{[3- (morpholin-4-yl) propyl] amino} imidazo [1,2-a] quinoxalin-1-yl) benzamide,
2-chloro-N-cyclopropyl-4- (8-fluoro-4-{[3- (2-oxopyrrolidin-1-yl) propyl] amino} imidazo [1,2-a] quinoxalin-1-yl) Benzamide,
2-chloro-N-cyclopropyl-4- {8-fluoro-4-[(pyridin-3-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
tert-butyl [3-({1- [3-chloro-4- (cyclopropylcarbamoyl) phenyl] -8-fluoroimidazo [1,2-a] quinoxalin-4-yl} amino) propyl] carbamate,
N-cyclopropyl-4- {7,8-difluoro-4-[(2-hydroxyethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide;
N-cyclopropyl-4- (7,8-difluoro-4-{[3- (2-oxopyrrolidin-1-yl) propyl] amino} imidazo [1,2-a] quinoxalin-1-yl) benzamide;
N-cyclopropyl-4- {7,8-difluoro-4-[(4-hydroxybutyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- {7,8-difluoro-4-[(2,2,2-trifluoroethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide;
4- {4-[(3-amino-3-oxopropyl) amino] -7,8-difluoroimidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
N-cyclopropyl-4- {4-[(2,3-dihydroxypropyl) amino] -7,8-difluoroimidazo [1,2-a] quinoxalin-1-yl} benzamide,
1- {4- [4- (butylamino) -7,8-difluoroimidazo [1,2-a] quinoxalin-1-yl] phenyl} -3-methylurea,
2-chloro-N-cyclopropyl-4- [7,8-difluoro-4- (propylamino) imidazo [1,2-a] quinoxalin-1-yl] benzamide,
2-chloro-N-cyclopropyl-4- {7,8-difluoro-4-[(pyridin-2-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide;
N-cyclopropyl-4- {4-[(4-hydroxybutyl) amino] -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- {4-[(3-methoxypropyl) amino] -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- (7,8-dimethyl-4-{[(1-methyl-1H-pyrazol-3-yl) methyl] amino} imidazo [1,2-a] quinoxalin-1-yl) benzamide ,
1- (4- {4-[(cyclopropylmethyl) amino] -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
1- [4- (7,8-dimethyl-4-{[(1-methyl-1H-pyrazol-5-yl) methyl] amino} imidazo [1,2-a] quinoxalin-1-yl) phenyl]- 3-methylurea,
2-chloro-N-cyclopropyl-4- {4-[(2-methoxyethyl) amino] -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl} benzamide,
4- {7-cyano-4-[(2-hydroxyethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
4- {7-cyano-4-[(3-methoxypropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
1- (4- {7-cyano-4-[(2-hydroxyethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
2-chloro-4- (7-cyano-4-{[3- (morpholin-4-yl) propyl] amino} imidazo [1,2-a] quinoxalin-1-yl) -N-cyclopropylbenzamide,
2-Chloro-4- (7-cyano-4-{[(1-methyl-1H-pyrazol-5-yl) methyl] amino} imidazo [1,2-a] quinoxalin-1-yl) -N-cyclo Propylbenzamide,
N-cyclopropyl-4- (8-fluoro-4-{[3- (morpholin-4-yl) propyl] amino} imidazo [1,2-a] quinoxalin-1-yl) benzamide;
N-cyclopropyl-4- {8-fluoro-4-[(4-hydroxybutyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- {4-[(cyclopropylmethyl) amino] -8-fluoroimidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- (8-fluoro-4-{[(1-methyl-1H-pyrazol-4-yl) methyl] amino} imidazo [1,2-a] quinoxalin-1-yl) benzamide;
1- [4- (8-Fluoro-4-{[3- (2-oxopyrrolidin-1-yl) propyl] amino} imidazo [1,2-a] quinoxalin-1-yl) phenyl] -3-methylurea ,
N- {2-[(8-fluoro-1- {4-[(methylcarbamoyl) amino] phenyl} imidazo [1,2-a] quinoxalin-4-yl) amino] ethyl} acetamide,
1- (4- {8-fluoro-4-[(pyridin-4-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
2-chloro-N-cyclopropyl-4- {8-fluoro-4-[(4-hydroxybutyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
2-Chloro-N-cyclopropyl-4- (8-fluoro-4-{[(1-methyl-1H-pyrazol-5-yl) methyl] amino} imidazo [1,2-a] quinoxalin-1-yl Benzamide,
N-cyclopropyl-4- {7,8-difluoro-4-[(3-fluorobenzyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide;
N-cyclopropyl-4- {7,8-difluoro-4-[(2-methylpropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide;
N-cyclopropyl-4- {7,8-difluoro-4-[(2-sulfamoylethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
2-chloro-N-cyclopropyl-4- {7,8-difluoro-4-[(2-methoxyethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
2-chloro-N-cyclopropyl-4- {7,8-difluoro-4-[(4-fluorobenzyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
2-chloro-N-cyclopropyl-4- {7,8-difluoro-4-[(4-hydroxybutyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
2-Chloro-N-cyclopropyl-4- (7,8-difluoro-4-{[(1-methyl-1H-pyrazol-3-yl) methyl] amino} imidazo [1,2-a] quinoxaline-1 -Il) benzamide,
N-cyclopropyl-4- {7,8-dimethyl-4-[(3-methylbutyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- {4-[(3-hydroxypropyl) amino] -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl} benzamide,
N-cyclopropyl-4- {7,8-dimethyl-4-[(pyridin-3-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide;
1- (4- {4-[(4-fluorobenzyl) amino] -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
1- (4- {4-[(4-hydroxybutyl) amino] -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
1- (4- {7,8-dimethyl-4-[(thiophen-2-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
1- (4- {7,8-dimethyl-4-[(pyridin-3-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
2-chloro-N-cyclopropyl-4- [4- (ethylamino) -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl] benzamide,
2-chloro-N-cyclopropyl-4- {4-[(3-methoxypropyl) amino] -7,8-dimethylimidazo [1,2-a] quinoxalin-1-yl} benzamide,
2-chloro-N-cyclopropyl-4- {7,8-dimethyl-4-[(2-sulfamoylethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} benzamide,
4- {7-cyano-4-[(pyridin-3-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
4- {7-cyano-4-[(furan-2-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
4- (7-cyano-4-{[(1-methyl-1H-pyrazol-3-yl) methyl] amino} imidazo [1,2-a] quinoxalin-1-yl) -N-cyclopropylbenzamide,
4- {7-cyano-4-[(2,3-dihydroxypropyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
1- (4- {7-cyano-4-[(3-methylbutyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
1- (4- {7-cyano-4-[(thiophen-2-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
1- [4- (7-cyano-4-{[3- (1H-imidazol-1-yl) propyl] amino} imidazo [1,2-a] quinoxalin-1-yl) phenyl] -3-methylurea,
1- (4- {7-cyano-4-[(furan-2-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} phenyl) -3-methylurea,
1- [4- (7-cyano-4-{[(1-methyl-1H-pyrazol-5-yl) methyl] amino} imidazo [1,2-a] quinoxalin-1-yl) phenyl] -3- Methylurea,
2-chloro-4- [7-cyano-4- (propylamino) imidazo [1,2-a] quinoxalin-1-yl] -N-cyclopropylbenzamide,
4- [4- (benzylamino) -7-cyanoimidazo [1,2-a] quinoxalin-1-yl] -2-chloro-N-cyclopropylbenzamide,
2-chloro-4- {7-cyano-4-[(thiophen-2-ylmethyl) amino] imidazo [1,2-a] quinoxalin-1-yl} -N-cyclopropylbenzamide,
4- {4-[(3-amino-3-oxopropyl) amino] -7-cyanoimidazo [1,2-a] quinoxalin-1-yl} -2-chloro-N-cyclopropylbenzamide A selected compound, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. General formula (4)

Wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined for the compound of general formula (I) in any one of claims 1 to 3 and Y is halogen Is an atom]
Intermediate compounds of the general formula: R ² -B (OH) ₂ or R ² -B (OC ₁ -C ₆ -alkyl) ₂
Wherein, R ² is as defined for the compounds of general formula (I) in claim 1]
With an intermediate compound of general formula (I)

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined for the compound of general formula (I) in any one of claims 1 to 3]
Method of manufacturing of providing compounds, set forth in any one of compounds of claims 1-3. 5. A compound according to any one of claims 1 to 4, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof for use in the treatment or prevention of disease. Or a composition comprising a mixture thereof . The composition of claim 6, wherein the salt is a pharmaceutically acceptable salt.   The compound according to any one of claims 1 to 4, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, a mixture thereof, and a pharmaceutical A pharmaceutical composition comprising an acceptable diluent or carrier.   The pharmaceutical composition according to claim 8, wherein the salt is a pharmaceutically acceptable salt. One or more compounds according to any one of claims 1 to 4 , or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof , Or the pharmaceutical composition of claim 8 , and
Docetaxel (Docetaxel) or Paclitaxel (Paclitaxel), Azepothilone B (Azaepothilone B) , Epothilone B (Epothilone B) or Sagopilone , Mitoxantrone, Predinisolone (Predinisolone), Dexamethasone (Dexamesone) Estramustin, Vinblastin, Vincristin, Doxorubicin, Idarubicin , Daunorubicin, Bleomycin, Etoposide, Cyclophosphamide, Cyphosphamide , Procarbazine, Melphalan, 5-Fluorouracil, Capecitabine, Fludarabine, Cytarabine , 2-chloro-2'-de Oxyadenosine, Thioguanine, Flutamide, Cyproterone acetate or Bicalutamide , Bortezomib, Cisplatin or Carboplatin , Chlorambucil and Chlorambucil A combination medicine comprising one or more drugs selected from Rituximab.   The combination medicine according to claim 10, wherein the salt is a pharmaceutically acceptable salt.   Disease prevention of the compound according to any one of claims 1 to 4, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof. Or use for the manufacture of a medicament for treatment.   Use according to claim 12, wherein the salt is a pharmaceutically acceptable salt.   14. Use according to claim 12 or 13, wherein the disease is a disease of uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response.   15. Use according to claim 14, wherein unregulated cell growth, proliferation and / or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is mediated by Mps-1.   15. Use according to claim 14, wherein the disease of uncontrolled cell growth, proliferation and / or survival, inappropriate cellular immune response or inappropriate cellular inflammatory response is a hematological tumor, solid tumor and / or metastasis thereof.   The diseases are leukemia and myelodysplastic syndrome; malignant lymphoma; head and neck tumors including brain tumors and brain metastases; breast tumors including non-small cell lung tumors and small cell lung tumors; gastrointestinal tumors; endocrine tumors; 15. Use according to claim 14, which is a gynecological tumor; a urological tumor including a renal tumor, a bladder tumor and a prostate tumor; a skin tumor; and a sarcoma; and / or a metastasis thereof. A general formula (4) for the preparation of a compound of general formula (I) according to any one of claims 1 to 3.

(Wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined for the compound of general formula (I) according to any one of claims 1 to 3, Y is a halogen atom).